back to the search page

Query Topic: Endothelial progenitor cell

Query Date:

endothelial cells(244)

ATPIF1 maintains normal mitochondrial structure which is impaired by CCM3 deficiency in endothelial cells.
Numerous signaling pathways have been demonstrated experimentally to affect the pathogenesis of cerebral cavernous malformations (CCM), a disease that can be caused by CCM3 deficiency. However, the understanding of the CCM progression is still limited. The objective of the present work was to elucidate the role of CCM3 by RNA-seq screening of CCM3 knockout mice. We found that ATPIF1 was decreased in siCCM3-treated Human Umbilical Vein Endothelial Cells (HUVECs), and the overexpression of ATPIF1 attenuated the changes in cell proliferation, adhesion and migration caused by siCCM3. The probable mechanism involved the conserved ATP concentration in mitochondria and the elongated morphology of the organelles. By using the CRISPR-cas9 system, we generated CCM3-KO Endothelial Progenitor Cells (EPCs) and found that the knockout of CCM3 destroyed the morphology of mitochondria, impaired the mitochondrial membrane potential and increased mitophagy. Overexpression of ATPIF1 contributed to the maintenance of normal structure of mitochondria, inhibiting activation of mitophagy and other signaling proteins (e.g., KLF4 and Tie2). The expression of KLF4 returned to normal in CCM3-KO EPCs after 2 days of re-overexpression of CCM3, but not other signaling proteins. ATPIF1 maintains the normal structure of mitochondria, inhibiting the activation of mitophagy and other signaling pathway in endothelial cells Loss of CCM3 leads to the destruction of mitochondria and activation of signaling pathways, which can be regulated by KLF4.
Publication Date: 2021-01-11 00:00:00
Journal: Cell & bioscience

circulating endothelial progenitor cells(135)

Circulating endothelial progenitor cells from septic patients are associated with different infectious organisms.
In sepsis, endothelial progenitor cells (EPCs) play a central role in the repair of endothelial injury by enhancing the processes of re-endothelialization and angiogenesis. However, the surface markers of EPCs have yet to be standardized, and Changes of EPCs in quantities and functions with different infectious organisms are still unclear. This study explored the relationship between the percentages of EPCs and various infectious organisms in patients with sepsis. Thirty-nine septic patients and 20 healthy controls were enrolled in this study. The percentages of CD34+/KDR+, CD133+/KDR+, CD34+/CD133+/KDR+, CD34+, CD133+, and KDR+ cells in different groups of septic patients and the healthy controls were analyzed by flow cytometry. The peripheral blood of septic patients had higher percentages of EPCs than that of the healthy controls. There were no significant differences in the percentages of EPCs between the sepsis and septic shock groups, nor between the survival group and the non-survival group. Additionally, the percentages of CD34+/CD133+/KDR+ cells in the gram-positive bacteremia group were significantly higher than those in the gram-negative bacteremia group and the negative blood culture group. The percentage of KDR+ cells in both the gram-positive bacteremia group and the gram-negative bacteremia group was significantly higher than that in the negative blood culture group. The percentages of circulating EPCs in patients with sepsis are associated with different infectious organisms.
Publication Date: 2021-02-07 00:00:00
Journal: Annals of palliative medicine


Hematopoietic Cell Transplantation for Sickle Cell Disease.
Sickle cell disease (SCD) is a severe autosomal recessively inherited disorder of the red blood cell characterized by erythrocyte deformation caused by the polymerization of the abnormal hemoglobin, which leads to erythrocyte deformation and triggers downstream pathological changes. These include abnormal rheology, vaso-occlusion, ischemic tissue damage, and hemolysis-associated endothelial dysfunction. These acute and chronic physiologic disturbances contribute to morbidity, organ dysfunction, and diminished survival. Hematopoietic cell transplantation (HCT) from HLA-matched or unrelated donors or haploidentical related donors or genetically modified autologous hematopoietic progenitor cells is performed with the intent of cure or long-term amelioration of disease manifestations. Excellent outcomes have been observed following HLA-identical matched related donor HCT. The majority of SCD patients do not have an available HLA-identical sibling donor. Increasingly, however, they have the option of undergoing HCT from unrelated HLA matched or related haploidentical donors. The preliminary results of transplantation of autologous hematopoietic progenitor cells genetically modified by adding a non-sickling gene or by genomic editing to increase expression of fetal hemoglobin are encouraging. These approaches are being evaluated in early-phase clinical trials. In performing HCT in patients with SCD, careful consideration must be given to patient and donor selection, conditioning and graft-vs.-host disease regimen, and pre-HCT evaluation and management during and after HCT. Sociodemographic factors may also impact awareness of and access to HCT. Further, there is a substantial decisional dilemma in HCT with complex tradeoffs between the possibility of amelioration of disease manifestations and early or late complications of HCT. The performance of HCT for SCD requires careful multidisciplinary collaboration and shared decision making between the physician and informed patients and caregivers.
Publication Date: 2021-01-21 00:00:00
Journal: Frontiers in pediatrics

circulating endothelial(193)

The Effect of Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors on Circulating Endothelial Progenitor Cells in Patients with Cardiovascular Disease.
Circulating endothelial progenitor cells (cEPCs) are vital to vascular repair by re-endothelialization. We aimed to explore the effect of proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) on cEPCs hypothesizing a possible pleiotropic effect. Patients with cardiovascular disease (CVD) were sampled for cEPCs at baseline and following the initiation of PCSK9i. cEPCs were assessed using flow cytometry by the expression of CD34 Our cohort included 26 patients (median age 68 (IQR 63, 73) years; 69% male). Following 3 months of treatment with PCSK9i and a decline in low-density lipoprotein cholesterol levels (153 (IQR 116, 176) to 56 (IQR 28, 72) mg/dl), p < 0.001), there was an increase in CD34 Patients with CVD treated with PCSK9i demonstrate higher levels of active cEPCs, reflecting the promotion of endothelial repair. These findings may represent a novel mechanism of action of PCSK9i.
Publication Date: 2021-01-05 00:00:00
Journal: Cardiovascular drugs and therapy

mesenchymal stem cells(108)

Cotransplantation of mesenchymal stem cells and endothelial progenitor cells for treating steroid-induced osteonecrosis of the femoral head.
Steroid-induced osteonecrosis of the femoral head (ONFH) is characterized by decreased osteogenesis, angiogenesis, and increased adipogenesis. While bone tissue engineering has been widely investigated to treat ONFH, its therapeutic effects remain unsatisfactory. Therefore, further studies are required to determine optimal osteogenesis, angiogenesis and adipogenesis in the necrotic area of the femoral head. In our study, we developed a carboxymethyl chitosan/alginate/bone marrow mesenchymal stem cell/endothelial progenitor cell (CMC/ALG/BMSC/EPC) composite implant, and evaluated its ability to repair steroid-induced ONFH. Our in vitro studies showed that BMSC and EPC coculture displayed enhanced osteogenic and angiogenic differentiation. When compared with single BMSC cultures, adipogenic differentiation in coculture systems was reduced. We also fabricated a three-dimensional (3D) CMC/ALG scaffold for loading cells, using a lyophilization approach, and confirmed its good cell compatibility characteristics, that is, high porosity, low cytotoxicity and favorable cell adhesion. 3D coculture of BMSCs and EPCs also promoted secretion of osteogenic and angiogenic factors. Then, we established an rabbit model of steroid-induced ONFH. The CMC/ALG/BMSC/EPC composite implant was transplanted into the bone tunnel of the rabbit femoral head after core decompression (CD) surgery. Twelve weeks later, radiographical and histological analyses revealed CMC/ALG/BMSC/EPC composite implants had facilitated the repair of steroid-induced ONFH, by promoting osteogenesis and angiogenesis, and reducing adipogenesis when compared with CD, CMC/ALG, CMC/ALG/BMSC and CMC/ALG/EPC groups. Thus, our data show that cotransplantation of BMSCs and EPCs in 3D scaffolds is beneficial in treating steroid-induced ONFH.
Publication Date: 2021-01-14 00:00:00
Journal: Stem cells translational medicine


Transplantation of retinal pigment epithelium and photoreceptors generated concomitantly via small molecule-mediated differentiation rescues visual function in rodent models of retinal degeneration.
Age-related macular degeneration (AMD) is a result of degeneration/damage of the retinal pigment epithelium (RPE) while retinitis pigmentosa (RP), an inherited early-onset disease, results from premature loss of photoreceptors. A promising therapeutic approach for both is the replacement of lost/damaged cells with human induced pluripotent stem cell (hiPSC)-derived retinal cells. The aim of this study was to investigate the in vivo function lity of RPE and photoreceptor progenitor (PRP) cells derived from a clinical-grade hiPSC line through a unified protocol. De novo-generated RPE and PRP were characterized extensively to validate their identity, purity, and potency. RPE expressed tight junction proteins, showed pigmentation and ciliation, and secreted polarization-related factors vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). PRP expressed neural retina proteins and cone and rod markers, and responded to KCl-induced polarization. Transcriptomic analysis demonstrated an increase in the expression of mature retinal tissue-specific genes coupled with concomitant downregulation of genes from undesired lineages. RPE transplantation rescued visual function in RCS rats shown via optokinetic tracking and photoreceptor rescue. PRP transplantation improved light perception in NOD.SCID-rd1 mice, and positive electroretinography signals indicated function l photoreceptor activity in the host's outer nuclear layer. Graft survival and integration were confirmed using immunohistochemistry, and no animals showed teratoma formation or any kind of ectopic growth in the eye. To our knowledge, this is the first demonstration of a unified, scalable, and GMP-adaptable protocol indicating strong animal efficacy and safety data with hiPSC-derived RPE and PRP cells. These findings provide robust proof-of-principle results for IND-enabling studies to test these potential regenerative cell therapies in patients.
Publication Date: 2021-01-21 00:00:00
Journal: Stem cell research & therapy

bone marrow(162)

A multi-niche microvascularized human bone marrow (hBM) on-a-chip elucidates key roles of the endosteal niche in hBM physiology.
The human bone marrow (hBM) is a complex organ critical for hematopoietic and immune homeostasis, and where many cancers metastasize. Understanding the fundamental biology of the hBM in health and diseases remain difficult due to complexity of studying or manipulating the BM in humans. Accurate biomaterial-based in vitro models of the hBM microenvironment are critical to further our understanding of the BM-niche and advancing new clinical interventions. Here we report a unique, 96-well format, microfluidic hBM-on-a-chip that incorporates the endosteal, central marrow, and perivascular niches of the human BM. Osteogenic differentiation of donor human mesenchymal stromal cells (MSCs) produced robust mineralization on the bottom surface ("bone-like endosteal layer") of the device, and subsequent seeding of human endothelial cells and MSCs in a fibrin-collagen hydrogel network ("central marrow") on the top created an interconnected 3D microvascular network ("perivascular niche"). The 96-well format allows eight independent "chips" to be studied in one plate, thereby increasing throughput and reproducibility. We show that this complex, multi-niche microtissue accurately mimics hBM composition and microphysiology, while providing key insights on hematopoietic progenitor dynamics. Presence of the endosteal niche decreased the proliferation and increased maintenance of CD34
Publication Date: 2021-02-09 00:00:00
Journal: Biomaterials

stem cell(163)

Detection of Endothelial Cell-Associated Human DNA Reveals Transplanted Human Bone Marrow Stem Cell Engraftment into CNS Capillaries of ALS Mice.
Repairing the altered blood-CNS-barrier in amyotrophic lateral sclerosis (ALS) is imperative to prevent entry of detrimental blood-borne substances into the CNS. Cell transplantation with the goal of replacing damaged endothelial cells (ECs) may be a new therapeutic approach for barrier restoration. We showed positive effects of human bone marrow-derived CD34+ cells (hBM34+) and endothelial progenitor cells (hBM-EPCs) intravenous transplantation into symptomatic G93A SOD1 mutant mice on barrier reparative processes. These benefits mainly occurred by administered cells engraftment into vascular walls in ALS mice; however, additional studies are needed to confirm cell engraftment within capillaries. The aim of this investigation was to determine the presence of human DNA within microvascular ECs isolated from the CNS tissues of G93A SOD1 mutant mice treated with human bone marrow-derived stem cell . The CNS tissues were obtained from previously cell-treated and media-treated G93A mice at 17 weeks of age. Real-time PCR (RT-PCR) assay for detection of human DNA was performed in ECs isolated from mouse CNS tissue. Viability of these ECs was determined using the LIVE/DEAD viability/cytotoxicity assay. Results showed appropriate EC isolation verified by immunoexpression of endothelial cell marker. Human DNA was detected in isolated ECs from cell-treated mice with greater concentrations in mice receiving hBM-EPCs vs. hBM34
Publication Date: 2021-02-06 00:00:00
Journal: Brain research bulletin


Prolonged oxygen exposure causes the mobilization and functional damage of stem or progenitor cells and exacerbates cardiac ischemia or reperfusion injury in healthy mice.
Oxygen is often administered to patients and occasionally to healthy individuals as well; however, the cellular toxicity of oxygen, especially following prolonged exposure, is widely known. To evaluate the potential effect of oxygen exposure on circulating stem/progenitor cells and cardiac ischemia/reperfusion (I/R) injury, we exposed healthy adult mice to 100% oxygen for 20 or 60 min. We then examined the c-kit-positive stem/progenitor cells and colony-forming cells and measured the cytokine/chemokine levels in peripheral blood. We also induced cardiac I/R injury in mice at 3 h after 60 min of oxygen exposure and examined the recruitment of inflammatory cells and the fibrotic area in the heart. The proportion of c-kit-positive stem/progenitor cells significantly increased in peripheral blood at 3 and 24 h after oxygen exposure for either 20 or 60 min (p < .01 vs. control). However, the abundance of colony-forming cells in peripheral blood conversely decreased at 3 and 24 h after oxygen exposure for only 60 min (p < .05 vs. control). Oxygen exposure for either 20 or 60 min resulted in significantly decreased plasma vascular endothelial growth factor levels at 3 h, whereas oxygen exposure for only 60 min reduced plasma insulin-like growth factor 1 levels at 24 h (p < .05 vs. control). Protein array indicated the increase in the levels of some cytokines/chemokines, such as CXCL6 (GCP-2) at 24 h after 60 min of oxygen exposure. Moreover, oxygen exposure for 60 min enhanced the recruitment of Ly6g- and CD11c-positive inflammatory cells at 3 days (p < .05 vs. control) and increased the fibrotic area at 14 days in the heart after I/R injury (p < .05 vs. control). Prolonged oxygen exposure induced the mobilization and functional impairment of stem/progenitor cells and likely enhanced inflammatory responses to exacerbate cardiac I/R injury in healthy mice
Publication Date: 2021-02-09 00:00:00
Journal: Journal of cellular physiology


Fenofibrate attenuates doxorubicin-induced cardiac dysfunction in mice via activating the eNOS/EPC pathway.
Endothelial progenitor cells (EPCs) improve endothelial impairment, which in turn restores endothelial function in patients with heart failure (HF). In the present study, we tested whether fenofibrate, with its anti-inflammatory and vasoprotective effects, could improve myocardial function by activating EPCs through the eNOS pathway in a doxorubicin (DOX)-induced cardiomyopathy mouse model. Wild-type mice were divided into 4 groups and treated with vehicle, DOX + saline, DOX + fenofibrate, and DOX + fenofibrate + L-NAME (N(ω)-nitro-L-arginine methyl ester). DOX-induced cardiac atrophy, myocardial dysfunction, the number of circulating EPCs and tissue inflammation were analyzed. Mice in the DOX + fenofibrate group had more circulating EPCs than those in the DOX + saline group (2% versus 0.5% of total events, respectively) after 4 weeks of treatment with fenofibrate. In addition, the inhibition of eNOS by L-NAME in vivo further abolished the fenofibrate-induced suppression of DOX-induced cardiotoxic effects. Protein assays revealed that, after DOX treatment, the differential expression of MMP-2 (matrix metalloproteinase-2), MMP-9 (matrix metalloproteinase-9), TNF-α (tumor necrosis factor-α), and NT-pro-BNP (N-terminal pro-B-type natriuretic peptide) between saline- and DOX-treated mice was involved in the progression of HF. Mechanistically, fenofibrate promotes Akt/eNOS and VEGF (vascular endothelial growth factor), which results in the activation of EPC pathway , thereby ameliorating DOX-induced cardiac toxicity.
Publication Date: 2021-01-15 00:00:00
Journal: Scientific reports


The effect of endothelial progenitor cell transplantation on neointimal hyperplasia and reendothelialisation after balloon catheter injury in rat carotid arteries.
Reendothelialisation is the natural pathway that inhibits neointimal hyperplasia and in-stent restenosis. Circulating endothelial progenitor cells (EPCs) derived from bone marrow (BM) might contribute to endothelial repair. However, the temporal and spatial distributions of reendothelialisation and neointimal hyperplasia after EPC transplantation in injured arteries are currently unclear. A carotid balloon injury (BI) model was established in Sprague-Dawley rats, and PKH26-labelled BM-derived EPCs were transplanted after BI. The carotid arteries were harvested on the first, fourth, seventh, and 14th day post- injury and analysed via light-sheet fluorescence microscopy and pathological staining (n = 3). EPC and human umbilical vein endothelial cell culture supernatants were collected, and blood samples were collected before and after transplantation. The paracrine effects of VEGF, IGF-1, and TGF-β1 in cell culture supernatants and serum were analysed by enzyme-linked immunosorbent assay (n = 4). Transplanted EPCs labelled with PKH26 were attached to the injured luminal surface the first day after BI. In the sham operation group, the transplanted EPCs did not adhere to the luminal surface. From the fourth day after BI, the mean fluorescence intensity of PKH26 decreased significantly. However, reendothelialisation and inhibition of neointimal hyperplasia were significantly promoted by transplanted EPCs. The degree of reendothelialisation of the EPC Transplanted EPCs had chemotactic enrichment and attached to the injured arterial luminal surface. Although decreasing significantly after the fourth day at the site of injury after transplantation, transplanted EPCs could still promote reendothelialisation and inhibit neointimal hyperplasia. The underlying mechanism is through paracrine cytokines and not differentiation into mature endothelial cells.
Publication Date: 2021-02-05 00:00:00
Journal: Stem cell research & therapy


Lymphangiogenesis in renal fibrosis arises from macrophages via VEGF-C/VEGFR3-dependent autophagy and polarization.
Inflammation plays a crucial role in the occurrence and development of renal fibrosis, which ultimately results in end-stage renal disease (ESRD). There is new focus on lymphangiogenesis in the field of inflammation. Recent studies have revealed the association between lymphangiogenesis and renal fibrosis, but the source of lymphatic endothelial cells (LECs) is not clear. It has also been reported that macrophages are involved in lymphangiogenesis through direct and indirect mechanisms in other tissues. We hypothesized that there was a close relationship between macrophages and lymphatic endothelial progenitor cells in renal fibrosis. In this study, we demonstrated that lymphangiogenesis occurred in a renal fibrosis model and was positively correlated with the degree of fibrosis and macrophage infiltration. Compared to resting (M0) macrophages and alternatively activated (M2) macrophages, classically activated (M1) macrophages predominantly transdifferentiated into LECs in vivo and in vitro. VEGF-C further increased M1 macrophage polarization and transdifferentiation into LECs by activating VEGFR3. It was suggested that VEGF-C/VEGFR3 pathway activation downregulated macrophage autophagy and subsequently regulated macrophage phenotype. The induction of autophagy in macrophages by rapamycin decreased M1 macrophage polarization and differentiation into LECs. These results suggested that M1 macrophages promoted lymphangiogenesis and contributed to newly formed lymphatic vessels in the renal fibrosis microenvironment, and VEGF-C/VEGFR3 signaling promoted macrophage M1 polarization by suppressing macrophage autophagy and then increased the transdifferentiation of M1 macrophages into LECs.
Publication Date: 2021-01-23 00:00:00
Journal: Cell death & disease

pluripotent stem cells(60)

A protocol for rapid pericyte differentiation of human induced pluripotent stem cells.
Pericytes play a critical role in promoting, regulating, and maintaining numerous vascular functions. Their dysfunction is a major contributor to the progression of vascular and neurodegenerative diseases, making them an ideal candidate for large-scale production for disease modeling and regenerative cell therapy. This protocol describes the rapid and robust differentiation of pericytes from human induced pluripotent stem cells (hiPSCs) while simultaneously generating a population of hiPSC-derived endothelial progenitor cells. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2017).
Publication Date: 2021-01-26 00:00:00
Journal: STAR protocols


Quality and Quantity-Cultured Human Mononuclear Cells Improve Human Fat Graft Vascularization and Survival in an In Vivo Murine Experimental Model.
Fat graft ischemia impedes us from having satisfying long-term results. The quality and quantity culture is a 1-week cell culture that increases the vasculogenic potential of peripheral blood mononuclear cells (PBMNC). This in vivo murine model investigates whether enrichment with quality and quantity-cultured human mononuclear cells (MNC-QQ) improves the vascularization in the human fat graft and whether this decreases the tissue loss. Human adipose tissue, PBMNC, MNC-QQ, and stromal vascular fraction were prepared. First, PBMNC, MNC-QQ, and stromal vascular fraction were compared in vitro for vasculogenic potential by endothelial progenitor cell colony-forming and culture assays. Second, 0.25-g fat grafts were created with 1 × 106 PBMNC (n = 16), 1 × 106 MNC-QQ (n = 16), 1 × 106 stromal vascular fraction (n = 16), or phosphate-buffered saline as control (n = 16) before grafting in BALB/c nude mice. Grafts were analyzed for weight persistence, vessel formation by CD31 immunohistochemistry, and angiogenic markers by quantitative polymerase chain reaction. MNC-QQ develop more definitive endothelial progenitor cell colonies and more functional endothelial progenitor cells compared to PBMNC and stromal vascular fraction. Weight persistence after 7 weeks was significantly higher in grafts with MNC-QQ (89.8 ± 3.5 percent) or stromal vascular fraction (90.1 ± 4.2 percent) compared with control (70.4 ± 6.3 percent; p < 0.05). MNC-QQ-enriched grafts had the highest vessel density (96.6 ± 6.5 vessels/mm2; control, 70.4 ± 5.6 vessels/mm2; p < 0.05). MNC-QQ exerted a direct vasculogenic effect through vascular integration and a potential paracrine vascular endothelial growth factor-mediated effect. Quality and quantity-cultured human mononuclear cells containing endothelial progenitor cells stimulate fat graft vascularization and enhance graft survival in a rodent recipient.
Publication Date: 2020-11-26 00:00:00
Journal: Plastic and reconstructive surgery


Current status of cardiac regenerative medicine; An update on point of view to cell therapy application.
Cardiovascular diseases (CVDs) are the leading cause of death globally. Because of the economic and social burden of acute myocardial infarction and its chronic consequences in surviving patients, understanding the pathophysiology of myocardial infarction injury is a major priority for cardiovascular research. MI is defined as cardiomyocytes death caused by an ischemic that resulted from the apoptosis, necrosis, necroptosis, and autophagy. The phases of normal repair following MI including inflammatory, proliferation, and maturation. Normal repair is slow and inefficient generally so that other treatments are required. Because of difficulties, outcomes, and backwashes of traditional therapies including coronary artery bypass grafting, balloon angioplasty, heart transplantation, and artificial heart operations, the novel strategy in the treatment of MI, cell therapy was newly emerged. In cell therapy a new population of cells has created that substitute with damaged cells. Different types of stem cell and progenitor cells have been shown to improve cardiac function through various mechanisms, including the formation of new myocytes, endothelial cells, and vascular smooth muscle cells. Bone marrow- and/or adipose tissue-derived mesenchymal stem cells, embryonic stem cells, autologous skeletal myoblasts, induced pluripotent stem cells, endothelial progenitor cells, cardiac progenitor cells and cardiac pericytes considered as a source for cell therapy In this study, we focused on the point of view of the cell sources.
Publication Date: 2021-01-30 00:00:00
Journal: Journal of cardiovascular and thoracic research


To be or not to be: endothelial cell plasticity in development, repair, and disease.
Endothelial cells display an extraordinary plasticity both during development and throughout adult life. During early development, endothelial cells assume arterial, venous, or lymphatic identity, while selected endothelial cells undergo additional fate changes to become hematopoietic progenitor, cardiac valve, and other cell types. Adult endothelial cells are some of the longest-lived cells in the body and their participation as stable components of the vascular wall is critical for the proper function of both the circulatory and lymphatic systems, yet these cells also display a remarkable capacity to undergo changes in their differentiated identity during injury, disease, and even normal physiological changes in the vasculature. Here, we discuss how endothelial cells become specified during development as arterial, venous, or lymphatic endothelial cells or convert into hematopoietic stem and progenitor cells or cardiac valve cells. We compare findings from in vitro and in vivo studies with a focus on the zebrafish as a valuable model for exploring the signaling pathways and environmental cues that drive these transitions. We also discuss how endothelial plasticity can aid in revascularization and repair of tissue after damage- but may have detrimental consequences under disease conditions. By better understanding endothelial plasticity and the mechanisms underlying endothelial fate transitions, we can begin to explore new therapeutic avenues.
Publication Date: 2021-01-16 00:00:00
Journal: Angiogenesis

myocardial infarction(79)

Soluble epoxide hydrolase inhibitors improve angiogenic function of endothelial progenitor cells via ERK/p38-mediated miR-126 upregulation in myocardial infarction mice after exercise.
It is well established that exercise could protect against myocardial infarction (MI). Previously, we found that epoxyeicosatrienoic acids (EETs) could be induced by exercise and has been found to protect against MI via promoting angiogenic function of endothelial progenitor cells (EPCs). However, the underling mechanism of EETs in promoting EPC functions is unclear. C57BL/6 mice were fed with a novel soluble epoxide hydrolase inhibitor (sEHi), TPPU, to increase EET levels, for 1 week before undergoing MI surgery. Mice were then subjected to exercise training for 4 weeks. Bone marrow-derived EPCs were isolated and cultured in vitro. Exercise upregulated miR-126 expression but downregulated the protein levels of its target gene, Spred1, in EPCs from MI mice. TPPU further enhanced the effects of exercise on EPCs. Spred1 overexpression abolished the protective effects of TPPU on EPC functions. Downregulation of miR-126 by antagomiR-126 impaired the inhibitor effects of TPPU on Spred1 mRNA and protein expression. Additionally, TPPU upregulated miR-126 is partially mediated through ERK/p38 MAPK pathway. This study showed that sEHi promoted miR-126 expression, which might be related to the beneficial effect of sEHi on EPC functions in MI mice under exercise conditions, by increasing ERK and p38 MAPK phosphorylation and inhibiting Spred1.
Publication Date: 2020-11-15 00:00:00
Journal: Experimental cell research


Retinoic Acid Benefits Glomerular Organotypic Differentiation from Adult Renal Progenitor Cells In Vitro.
When in certain culture conditions, organotypic cultures are able to mimic developmental stages of an organ, generating higher-order structures containing functional subunits and progenitor niches. Despite the major advances in the area, researchers have not been able to fully recapitulate the complexity of kidney tissue. Pluripotent stem cells are extensively used in the field, but very few studies make use of adult stem cells. Herein, we describe a simple and feasible method for achieving glomerular epithelial differentiation on an organotypic model comprising human renal progenitor cells from adult kidney (hRPCs). Their glomerular differentiative potential was studied using retinoic acid (RA), a fundamental molecule for intermediate mesoderm induction on early embryogenesis. Immunofluorescence, specific cell surface markers expression and gene expression analysis confirm the glomerular differentiative potential of RA in a short-term culture. We also compared the potential of RA with a potent WNT agonist, CHIR99021, on the differentiative capacity of hRPCs. Gene expression and immunofluorescence analysis confirmed that hRPCs are more sensitive to RA stimulation when compared to CHIR9901. Endothelial cells were also included on the spheroids, resulting in a higher organizational level. The assembly potential of these cells and their selective stimulation will give new insights on adult organotypic cell culture studies and will hopefully guide more works in this important area of research.
Publication Date: 2021-02-05 00:00:00
Journal: Stem cell reviews and reports


Optimizing the recovery of peripheral blood mononuclear cells trapped in leukoreduction filters - A comparison study.
The isolation of captured peripheral blood mononuclear cells (PBMNCs) from leukoreduction filters (LRFs) can be of great importance in terms of bringing the lost cells back into use. The aim of this study was to evaluate various methods based on their potential to recover the peripheral blood cells from LRFs with a focus on mononuclear cells (MNCs). For cell isolation from LRFs, three distinct methods (back-flushing, direct and vacuum pump) were compared through the calculation of the yield of isolated MNCs. The viability of extracted cells was determined by the flow cytometry technique. Moreover, the recovered MNCs were characterized regarding the presence of blood stem cell purification. The cell culture, microscopic observation, and immunophenotyping were employed to characterize the blood stem cells (hematopoietic, mesenchymal and progenitor endothelial stem cells). The yield of isolation obtained in the back-flushing, direct and vacuum pump methods were 17.7 ± 1.28, 17.3 ± 0.96 and 21.2 ± 0.90 percent, respectively. Although the highest potential for total blood cell recovery belonged to the vacuum pump method, the lowest cell viability (85.73 ± 4.84%) was observed in this method. However, the isolation process of the back-flushing and direct methods had less effect on cell viability. The characterization of the isolated MNCs displayed that the dominant positive phenotype was for CD34/CD45, indicating hematopoietic stem cells. In addition, the endothelial stem/progenitor cells were significantly detected as CD31/CD133 positive cells. According to our results and considering the safety and efficiency potential of each of the applied methods, the back-flushing in comparison with the other methods can be considered a suitable procedure for MNC isolation from LRFs.
Publication Date: 2021-01-12 00:00:00
Journal: Hematology, transfusion and cell therapy


Effects of normobaric cyclic hypoxia exposure on mesenchymal stem-cell differentiation-pilot study on bone parameters in elderly.
Mesenchymal stem cells (MSC) of bone marrow are the progenitor of osteoblasts and adipocytes. MSC tend to differentiate into adipocytes, instead of osteoblasts, with aging. This favors the loss of bone mass and development of osteoporosis. Hypoxia induces hypoxia inducible factor 1α gene encoding transcription factor, which regulates the expression of genes related to energy metabolism and angiogenesis. That allows a better adaptation to low O To evaluate the CH effect on MSC differentiation, and whether it improves bone mineral density in elderly. MSC cultures were induced to differentiate into osteoblasts or adipocytes, in CH (3% O CH (4 h of hypoxic exposure) inhibited extracellular matrix mineralization and lipid-droplet formation in MSC induced to differentiate into osteoblasts or adipocytes, respectively. However, both parameters were not significantly affected by the other shorter hypoxia times assessed. The longest periods of hypoxia downregulated the expression of genes related to extracellular matrix formation, in MSC induced to differentiate into osteoblasts. Interestingly, osteocalcin (associated to energy metabolism) was upregulated. Vascular endothelial growth factor an expression and low-density lipoprotein receptor related protein 5/6/dickkopf Wnt signaling pathway inhibitor 1 (associated to Wnt/β-catenin pathway activation) increased in osteoblasts. Yet, they decreased in adipocytes after CH treatments, mainly with the longest hypoxia times. However, the same CH treatments increased the osteoprotegerin/receptor activator for nuclear factor kappa B ligand ratio in both cell types. An increase in total bone mineral density was observed in elderly people exposed to CH, but not in specific regions. The percentage of fat did not vary between groups. CH may have positive effects on bone health in the elderly, due to its possible inhibitory effect on bone resorption, by increasing the osteoprotegerin / receptor activator for nuclear factor kappa B ligand ratio.
Publication Date: 2021-01-29 00:00:00
Journal: World journal of stem cells

coronary artery disease(49)

Shear stress improves the endothelial progenitor cell function via the CXCR7/ERK pathway axis in the coronary artery disease cases.
Dysfunction in the late Endothelial Progenitor Cells (EPCs) is responsible for endothelial repair in patients with Coronary Artery Disease (CAD), and the shear stress is beneficial for EPCs function. However, the impact of shear stress on the capacity of EPCs in CAD patients has not been elucidated yet. The C-X-C chemokine receptor 7/extracellular signal-regulated kinase (CXCR7)/(ERK) pathways are identified to regulate EPCs function in CAD patients. Here, we hypothesize that shear stress upregulates the CXCR7/ERK pathways, which restore the EPCs function in CAD patients. The human Peripheral Blood Mononuclear Cells (PBMCs) were collected from healthy adults and CAD patients and then used for EPCs cultivation. The Lv-siRNA for human CXCR7 was transfected into induced EPCs isolated from the CAD patients. Meanwhile, the EPCs from CAD patients were subjected to shear stress generated by a biomimetic device. Next, the cell viability, migration, tube formation, and apoptosis were detected by CCK-8, Transwell assay, Matrigel, and flow cytometry, respectively. Also, the CXCR7/ERK pathways in human EPCs were analyzed by Western blotting and qRT-PCR. Compared to the EPCs collected from normal adults, the CAD patient-derived EPCs showed reduced in vitro vasculogenic capacity. Also, the level of CXCR7 in CAD patient-derived EPCs was significantly reduced compared to the EPCs of healthy subjects. Meanwhile, the extracellular signal-regulated kinase (ERK), which represents a CXCR7 downstream signaling pathway, had decreased phosphorylation level. The shear stress treatment augmented the CXCR7 expression and also elevated ERK phosphorylation, which is comparable to the up-regulation of CAD patient-derived EPCs function. Further, the small interfering RNA (siRNA)-mediated CXCR7 knockdown diminished the enhanced migration, adhesion, and tube formation capacity of shear stress treated CAD patient-derived EPCs. Up-regulation of the CXCR7/ERK pathways by shear stress can be a promising new target in enhancing the vasculogenic ability of CAD patient-derived EPCs.
Publication Date: 2020-09-08 00:00:00
Journal: BMC cardiovascular disorders

growth factor(93)

Cyclic Stretch Induces Vascular Smooth Muscle Cells to Secrete Connective Tissue Growth Factor and Promote Endothelial Progenitor Cell Differentiation and Angiogenesis.
Endothelial progenitor cells (EPCs) play a vital role in endothelial repair following vascular injury by maintaining the integrity of endothelium. As EPCs home to endothelial injury sites, they may communicate with exposed vascular smooth muscle cells (VSMCs), which are subjected to cyclic stretch generated by blood flow. In this study, the synergistic effect of cyclic stretch and communication with neighboring VSMCs on EPC function during vascular repair was investigated.
Publication Date: 2020-12-29 00:00:00
Journal: Frontiers in cell and developmental biology


Stem Cell-based Dental Pulp Regeneration: Insights From Signaling Pathways.
Deep caries, trauma, and severe periodontitis result in pulpitis, pulp necrosis, and eventually pulp loss. However, no clinical therapy can regenerate lost pulp. A novel pulp regeneration strategy for clinical application is urgently needed. Signaling transduction plays an essential role in regulating the regenerative potentials of dental stem cells. Cytokines or growth factors, such as stromal cell-derived factor (SDF), fibroblast growth factor (FGF), bone morphogenetic protein (BMP), vascular endothelial growth factor (VEGF), WNT, can promote the migration, proliferation, odontogenic differentiation, pro-angiogenesis, and pro-neurogenesis potentials of dental stem cells respectively. Using the methods of signaling modulation including growth factors delivery, genetic modification, and physical stimulation has been applied in multiple preclinical studies of pulp regeneration based on cell transplantation or cell homing. Transplanting dental stem cells and growth factors encapsulated into scaffold regenerated vascularized pulp-like tissue in the root canal. Also, injecting a flowable scaffold only with chemokines recruited endogenous stem/progenitor cells for pulp regeneration Notably, dental pulp regeneration has gradually developed into the clinical phase. These findings enlightened us on a novel strategy for structural and functional pulp regeneration through elaborate modulation of signaling transduction spatially and temporally via clinically applicable growth factors delivery. But challenges, such as the adverse effects of unphysiological signaling activation, the controlled drug release system, and the safety of gene modulation, are necessary to be tested in future works for promoting the clinical translation of pulp regeneration
Publication Date: 2021-01-19 00:00:00
Journal: Stem cell reviews and reports

stem progenitor cells(56)

Glucocorticoid guides mobilization of bone marrow stem/progenitor cells via FPR and CXCR4 coupling.
Our previous studies have proved the efficient exogenous repairing responses via bone marrow stem and progenitor cells (BMSPCs). However, the trafficking of endogenous bone marrow stem and progenitor cells to and from the bone marrow (BM) is a highly regulated process that remains to be elucidated. We aimed to study the relative importance of the hypothalamic-pituitary-adrenal (HPA) axis in the glucocorticoid-induced BMSPC mobilization. The circulating mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) were examined in Crh (+/+, -/-) mice after running stress or glucocorticoid mini-infusion. The MSCs and EPCs were investigated ex vivo after treatment with glucocorticoid and glucocorticoid receptor (GR) antagonist, RU486. The expression of chemotaxis receptors, N-formyl peptide receptor (FPR), and Cys-X-Cys receptor 4 (CXCR4) of MSCs and EPCs as well as their colocalization were investigated after treatment with glucocorticoid, glucocorticoid receptor (GR) antagonist (RU486), and FPR antagonist (Cyclosporin H). Forced running stress increased circulating MSCs and EPCs in mice, which was blunted when Crh was knocked out, and positively related to the levels of serum glucocorticoid. Prolonged glucocorticoid mini-infusion imitated the stress-induced increase in circulating MSCs and EPCs in Crh Glucocorticoid-induced CXCR4-FPR responsiveness selectively guides the mobilization of BMSPCs, which is essential to functional tissue repair. Schematic view of the role of glucocorticoid on the mobilization of bone marrow-derived stem/progenitor cells subsets in the present study. The HPA axis activation promotes the release of glucocorticoid, which regulates the directional migration of MSCs and EPCs mainly via GR. The possible mechanisms refer to the signal coupling of FPR and CXCR4. Their two-sided changes regulated by glucocorticoid are involved in the egress of MSCs and EPCs from BM, which is helpful for wound healing. MSCs, mesenchymal stem cells; EPCs, endothelial progenitor cells.
Publication Date: 2021-01-09 00:00:00
Journal: Stem cell research & therapy


Autonomous TGFβ signaling induces phenotypic variation in human acute myeloid leukemia.
Heterogeneity of leukemia stem cells (LSCs) is involved in their collective chemoresistance. To eradicate LSCs, it is necessary to understand the mechanisms underlying their heterogeneity. Here, we aimed to identify signals responsible for heterogeneity and variation of LSCs in human acute myeloid leukemia (AML). Monitoring expression levels of endothelial cell-selective adhesion molecule (ESAM), a hematopoietic stem cell-related marker, was useful to detect the plasticity of AML cells. While healthy human hematopoietic stem/progenitor cells robustly expressed ESAM, AML cells exhibited heterogeneous ESAM expression. Interestingly, ESAM
Publication Date: 2021-02-05 00:00:00
Journal: Stem cells (Dayton, Ohio)

endothelial colony-forming cells(57)

Differential Angiogenic Responses of Human Endothelial Colony-Forming Cells to Different Molecular Subtypes of Breast Cancer Cells.
Triple negative breast cancer (TNBC) is one subtype of breast cancer. It is characterized by lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Compared with non-TNBC, TNBC is more aggressive, of higher grade, and frequently metastatic with poor prognosis, which is correlated with upregulated microvascular density. Endothelial colony-forming cells (ECFCs) mediate neovascularization, which is the crucial contributor to cancer growth and metastasis. The present study aimed to determine whether angiogenic responses of ECFCs are regulated differently by TNBC compared with non-TNBC. MDA-MB-231 and MCF7 cells were utilized for TNBC and non-TNBC, respectively. Bone-marrow-derived human ECFCs were treated with a conditioned medium (CM) of cancer cells to investigate the paracrine effect on angiogenesis. Also, ECFCs were co-cultured with cancer cells to evaluate the angiogenic effect of direct cell-to-cell interaction. Angiogenic responses of ECFCs were evaluated by proliferation, migration, and tube formation. Gene expression profiles of pro-angiogenic factors were also analyzed. Migration and tube formation of ECFCs were increased by treatment with CM of MDA-MB-231, which correlated with a higher gene expression profile of pro-angiogenic factors in MDA-MB-231 compared to MCF7. Interestingly, ECFCs co-cultured with MDA-MB-231 showed further increase of tube formation, suggesting synergic mechanisms between the paracrine effect and direct interaction between the cells. The angiogenic potential of ECFCs was enhanced by TNBC through both direct and indirect mechanisms. Therefore, the investigation of signaling pathways to regulate ECFC-mediated angiogenesis will be important to the discovery of anti-angiogenic therapies to treat TNBC patients.
Publication Date: 2021-02-05 00:00:00
Journal: Journal of lipid and atherosclerosis


Human foreskin-derived dermal stem/progenitor cell-conditioned medium combined with hyaluronic acid promotes extracellular matrix regeneration in diabetic wounds.
Diabetic wounds remain a challenging clinical problem, which requires further treatment development. Published data showed that dermis-derived stem/progenitor cells (DSPCs) display superior wound healing in vitro. The beneficial effects of DSPCs are mediated through paracrine secretion, which can be obtained from conditioned medium (CM). Hyaluronic acid (HA) is especially suitable for skin regeneration and delivering bioactive molecules in CM. This study investigated the effect of human foreskin-derived dermal stem/progenitor cell (hFDSPC)-CM combined with HA on a diabetic mouse model and relevant mechanism in vitro. hFDSPCs and human adipose-derived stem cells (hADSCs) were identified, and the respective CM was prepared. PBS, HA, hFDSPC-CM combined with HA, or hADSC-CM combined with HA was topically applied to mice. HE, CD31, CD68, CD86, and CD206 staining was performed to evaluate gross wound condition, angiogenesis, and inflammation, respectively. Masson and Picrosirius red staining was performed to evaluate collagen deposition and maturation. The effects of hFDSPC-CM and hADSC-CM on human keratinocyte cells (HaCaT) and fibroblasts were evaluated in vitro using CCK-8 and EdU assays to determine cell viability and proliferation, respectively. The scratch assay was performed to evaluate cell migration. Tube formation assay was performed on human umbilical vein endothelial cells (HUVECs) to confirm angiogenesis. Extracellular matrix (ECM) metabolic balance-related genes and proteins, such as collagen I (COL 1), collagen III (COL 3), fibronectin (FN), α-SMA, matrix metalloproteinases 1 (MMP-1), matrix metalloproteinases 3 (MMP-3), and transforming growth factor-beta 1 (TGF-β1), were analysed. hFDSPC-CM combined with HA showed superior wound closure rate over hADSC-CM. Histologically, the hFDSPC-CM combined with HA group showed significantly improved re-epithelialisation, angiogenesis, anti-inflammation, collagen regeneration, and maturation compared to hADSC-CM combined with HA group. In vitro assays revealed that hFDSPC-CM displayed significant advantages on cell proliferation, migration, and ECM regeneration through a TGF-β/Smad signalling pathway compared with hADSC-CM. hFDSPC-CM combined with HA was superior for treating diabetic wounds. The underlying mechanism may promote proliferation and migration of epidermal cells with fibroblasts, thus leading to ECM deposition and remodelling. Reduced inflammation may be due to the above-mentioned mechanism.
Publication Date: 2021-01-11 00:00:00
Journal: Stem cell research & therapy


Endothelial progenitor cells promote osteogenic differentiation in co-cultured with mesenchymal stem cells via the MAPK-dependent pathway.
The role of bone tissue engineering is to regenerate tissue using biomaterials and stem cell-based approaches. Combination of two or more cell types is one of the strategies to promote bone formation. Endothelial progenitor cells (EPCs) may enhance the osteogenic properties of mesenchymal stem cells (MSCs) and promote bone healing; this study aimed to investigate the possible mechanisms of EPCs on promoting osteogenic differentiation of MSCs. MSCs and EPCs were isolated and co-cultured in Transwell chambers, the effects of EPCs on the regulation of MSC biological properties were investigated. Real-time PCR array, and western blotting were performed to explore possible signaling pathways involved in osteogenesis. The expression of osteogenesis markers and calcium nodule formation was quantified by qRT-PCR, western blotting, and Alizarin Red staining. Results showed that MSCs exhibited greater alkaline phosphatase (ALP) activity and increased calcium mineral deposition significantly when co-cultured with EPCs. The mitogen-activated protein kinase (MAPK) signaling pathway was involved in this process. p38 gene expression and p38 protein phosphorylation levels showed significant upregulation in co-cultured MSCs. Silencing expression of p38 in co-cultured MSCs reduced osteogenic gene expression, protein synthesis, ALP activity, and calcium nodule formation. These data suggest paracrine signaling from EPCs influences the biological function and promotes MSCs osteogenic differentiation. Activation of the p38MAPK pathway may be the key to enhancing MSCs osteogenic differentiation via indirect interactions with EPCs.
Publication Date: 2020-12-15 00:00:00
Journal: Stem cell research & therapy


Fetal sheep support the development of hematopoietic cells in vivo from human induced pluripotent stem cells.
We report that a sheep fetal liver provides a microenvironment for generating hematopoietic cells with long-term engrafting capacity and multilineage differentiation potential from human induced pluripotent stem cell (iPSC)-derived hemogenic endothelial cells (HEs). Despite the promise of iPSCs for making any cell types, generating hematopoietic stem and progenitor cells (HSPCs) is still a challenge. We hypothesized that the hematopoietic microenvironment, which exists in fetal liver but is lacking in vitro, turns iPSC-HEs into HSPCs. To test this, we transplanted CD45-negative iPSC-HEs into fetal sheep liver, in which HSPCs first grow. Within 2 months, the transplanted cells became CD45 positive and differentiated into multilineage blood cells in the fetal liver. Then, CD45-positive cells translocated to the bone marrow and were maintained there for 3 years with the capability of multilineage differentiation, indicating that hematopoietic cells with long-term engraftment potential were generated. Moreover, human hematopoietic cells were temporally enriched by xenogeneic donor-lymphocyte infusion into the sheep. This study could serve as a foundation to generate HSPCs from iPSCs.
Publication Date: 2021-01-05 00:00:00
Journal: Experimental hematology

hematopoietic stem(101)

Hematopoietic Stem Cell Niches and Signals Controlling Immune Cell Development and Maintenance of Immunological Memory.
Studies over the last couple of decades have shown that hematopoietic stem cells (HSCs) are critically dependent on cytokines such as Stem Cell Factor and other signals provided by bone marrow niches comprising of mesenchymal stem and progenitor cells (MSPCs) and endothelial cells (ECs). Because of their critical roles in HSC maintenance the niches formed by MSPCs and ECs are commonly referred to as HSC niches. For the most part, the signals required for HSC maintenance act in a short-range manner, which imposes the necessity for directional and positional cues in order for HSCs to localize and be retained properly in stem cell niches. The chemokine CXCL12 and its Gαi protein coupled receptor CXCR4, besides promoting HSC quiescence directly, also play instrumental roles in enabling HSCs to access bone marrow stem cell niches. Recent studies have revealed, however, that HSC niches also provide a constellation of hematopoietic cytokines that are critical for the production of most, if not all, blood cell types. Some hematopoietic cytokines, namely IL-7 and IL-15 produced by HSC niches, are not only required for lymphopoiesis but are also essential for memory T cell maintenance. Consequently, hematopoietic progenitors and differentiated immune cells, such as memory T cell subsets, also depend on the CXCL12/CXCR4 axis for migration into bone marrow and interactions with MSPCs and ECs. Similarly, subsets of antibody-secreting plasma cells also reside in close association with CXCL12-producing MSPCs in the bone marrow and require the CXCR4/CXCL12 axis for survival and long-term maintenance. Collectively, these studies demonstrate a broad range of key physiological roles, spanning blood cell production and maintenance of immunological memory, that are orchestrated by stem cell niches through a common and simple mechanism: CXCL12/CXCR4-mediated cell recruitment followed by receipt of a maintenance and/or instructive signal. A fundamental flaw of this type of cellular organization is revealed by myeloid and lymphoid leukemias, which target stem cell niches and induce profound transcriptomic changes that result in reduced hematopoietic activity and altered mesenchymal cell differentiation.
Publication Date: 2020-12-17 00:00:00
Journal: Frontiers in immunology

peripheral blood(77)

A pre-conditioning protocol of peripheral blood derived endothelial colony forming cells for endothelialization of tissue engineered constructs.
In regenerative medicine, autologous endothelial colony forming cells (ECFCs) bear the greatest potential to be used for surface endothelialization of tissue engineered constructs, as they are easily attainable and possess a high proliferation rate. The aim of this study was to develop a standardized pre-conditioning protocol under dynamic conditions simulating the physiology of human circulation to improve the formation of a flow resistant monolayer of ECFCs and to enhance the antithrombogenicity of the endothelial cells. The main focus of the study was to consequently compare the cellular behavior under a steady laminar flow against a pulsatile flow. Mononuclear cells were isolated out of peripheral blood (PB) buffy coats and plated on uncoated tissue culture flasks in anticipation of guidelines for Advanced Therapy Medicinal Products. ECFCs were identified by typical surface markers such as CD31, CD146 and VE-Cadherin. To explore the effects of dynamic cultivation, ECFCs and human umbilical vein endothelial cells were comparatively cultured under either laminar or pulsatile (1 Hz) flow conditions with different grades of shear stress (5 dyn/cm
Publication Date: 2020-11-20 00:00:00
Journal: Microvascular research

type 2 diabetes(44)

Acute effects of sitagliptin on progenitor cells and soluble mediators in newly diagnosed type 2 diabetes.
Studies have confirmed that endothelial progenitor cells (EPCs) are involved in diabetic complications. The present study assessed the action of the dipeptidyl peptidase-4 inhibitor sitagliptin on EPCs in newly diagnosed type 2 diabetes patients. 60 newly-diagnosed type 2 diabetes patients were randomly divided into three treatment groups: sitagliptin (n = 20), metformin (n = 20), and combination sitagliptin and metformin (n = 20). Patients were treated once daily for 3 days. Before and after each treatment, the number of EPCs and concentration of soluble mediators (glucagon-like peptide 1 (GLP-1), nitric oxide (NO), endothelin-1 (ET-1), and stromal cell-derived factor-1α (SDF-1α)) were determined. The number of CD34 Sitagliptin is able to directly increase the number of peripheral blood EPCs. This direct effect is to be important for lowering vascular risk in early diabetes before macrovascular complications appear.
Publication Date: 2020-06-23 00:00:00
Journal: International journal of clinical pharmacology and therapeutics

wound healing(75)

Beneficial Effects of Astragaloside IV-Treated and 3-Dimensional-Cultured Endothelial Progenitor Cells on Angiogenesis and Wound Healing.
Astragaloside IV (AS-IV) is a natural herb extract and a popular compound used in traditional Chinese medicine because of its effect on multiple biological processes, such as promotion of cell proliferation, improvement in cardiopulmonary and vascular function, and promotion of angiogenesis around wounds, leading to accelerated wound healing Vascular regeneration primarily results from the differentiation of endothelial progenitor cells (EPCs). Biomedical acceleration of angiogenesis and differentiation of EPCs around the wound remain challenging. In this study, we treated human umbilical cord blood-derived EPCs with AS-IV and cultured them on 2-dimensional (tissue culture polystyrene) and 3-dimensional culture plates (3DPs). These cultured cells were then combined with human blood plasma gel and applied on the skin of nude mice in an attempt to repair full-thickness skin defects. The results show that using 3DP culture could increase vascular-related gene expression in EPCs. Furthermore, 12.5 μg/mL AS-IV-treaded EPCs were combined with plasma gels (P-3DP-EPC12.5) and showed enhanced vascular-related protein expression levels after 3 days of culture. Finally, P-3DP-EPC12.5s were used to repair full-thickness skin defects in nude mice, and we could register a wound healing rate greater than 90% by day 14. Based on these results, we concluded that we have developed a potential therapeutic approach for wound healing using plasma gel containing 3-dimensional surface-cultured AS-IV-treated EPCs.
Publication Date: 2021-01-14 00:00:00
Journal: Annals of plastic surgery

pluripotent stem(93)

Human endothelial colony-forming cells provide trophic support for pluripotent stem cell-derived cardiomyocytes via distinctively high expression of neuregulin-1.
The search for a source of endothelial cells (ECs) with translational therapeutic potential remains crucial in regenerative medicine. Human blood-derived endothelial colony-forming cells (ECFCs) represent a promising source of autologous ECs due to their robust capacity to form vascular networks in vivo and their easy accessibility from peripheral blood. However, whether ECFCs have distinct characteristics with translational value compared to other ECs remains unclear. Here, we show that vascular networks generated with human ECFCs exhibited robust paracrine support for human pluripotent stem cell-derived cardiomyocytes (iCMs), significantly improving protection against drug-induced cardiac injury and enhancing engraftment at ectopic (subcutaneous) and orthotopic (cardiac) sites. In contrast, iCM support was notably absent in grafts with vessels lined by mature-ECs. This differential trophic ability was due to a unique high constitutive expression of the cardioprotective growth factor neuregulin-1 (NRG1). ECFCs, but not mature-ECs, were capable of actively releasing NRG1, which, in turn, reduced apoptosis and increased the proliferation of iCMs via the PI3K/Akt signaling pathway. Transcriptional silencing of NRG1 abrogated these cardioprotective effects. Our study suggests that ECFCs are uniquely suited to support human iCMs, making these progenitor cells ideal for cardiovascular regenerative medicine.
Publication Date: 2021-01-18 00:00:00
Journal: Angiogenesis


Diabetes pharmacotherapy and circulating stem/progenitor cells. State of the art and evidence gaps.
Diabetes is burdened with the development of several end-organ complications leading to excess mortality. Though the causes of such organ damage are far from being clarified, diabetes has been redefined as a disease of impaired damage control, wherein ongoing damage is not adequately compensated by activation of repair processes. Bone marrow-derived hematopoietic stem/progenitor cells (HSPCs) and their descendants endothelial progenitor cells (EPCs) have been extensively studied as major players in tissue homeostasis as well as biomarkers of diabetic complication risk. Thus, strategies to raise the levels of circulating HSPCs/EPCs have attracted interest for their potential to modify the future risk of complications. We herein discuss state-of-the-art of the effects exerted by diabetes pharmacotherapy on such cell populations. Further, we highlight which outstanding questions remain to be addressed for a more comprehensive understanding of this topic.
Publication Date: 2020-12-04 00:00:00
Journal: Current opinion in pharmacology


MicroRNA-139-5p upregulation is associated with diabetic endothelial cell dysfunction by targeting c-jun.
Dysfunction of endothelial cells (ECs) and their progenitor cells is an important feature of diabetic vascular disease. MicroRNA (miR)-139-5p is involved in inhibiting the metastasis and progression of diverse malignancies. However, the role of miR-139-5p in ECs still remains unclarified. Here we demonstrated that miR-139-5p expression was elevated in endothelial colony-forming cells (ECFCs) isolated from patients with diabetes, ECs derived from the aorta of diabetic rodents, and human umbilical vein endothelial cells (HUVECs) cultured in high glucose media. MiR-139-5p mimics inhibited tube formation, migration, proliferation, and down-regulated expression of c-jun, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF)-B, in ECFCs and HUVECs, respectively; moreover, miR-139-5p inhibitors reversed the tendency. Further, gain- and-loss function experiments and ChIP assay indicated that miR-139-5p regulate functions of ECFCs by targeting c-jun-VEGF/PDGF-B pathway.
Publication Date: 2020-12-10 00:00:00
Journal: Aging


The acute and long-term effects of a cardiac rehabilitation program on endothelial progenitor cells in chronic heart failure patients: Comparing two different exercise training protocols.
Vascular endothelial dysfunction is an underlying pathophysiological feature of chronic heart failure (CHF). Endothelial progenitor cells (EPCs) are also impaired. The purpose of the study was to assess the effect of a cardiac rehabilitation (CR) program on the increase of EPCs at rest and on the acute response after maximal exercise in patients with CHF and investigate whether there were differences between two exercise training protocols and patients of NYHA II and III classes. Forty-four patients with stable CHF enrolled in a 36-session CR program and were randomized in one training protocol; either high-intensity interval training (HIIT) or HIIT combined with muscle strength (COM). All patients underwent maximum cardiopulmonary exercise testing (CPET) before and after the CR program and venous blood was drawn before and after each CPET. Five endothelial cellular populations, expressed as cells/10 An increase in all endothelial cellular populations at rest was observed after the CR program (p < 0.01). The acute response after maximum exercise increased in 4 out of 5 endothelial cellular populations after rehabilitation. Although there was increase in EPCs at rest and the acute response after rehabilitation in each exercise training group and each NYHA class, there were no differences between HIIT and COM groups or NYHA II and NYHA III classes (p > 0.05). A 36-session CR program increases the acute response after maximum CPET and stimulates the long-term mobilization of EPCs at rest in patients with CHF. These benefits seem to be similar between HIIT and COM exercise training protocols and between patients of different functional classes.
Publication Date: 2021-01-05 00:00:00
Journal: International journal of cardiology. Heart & vasculature

bone marrow-derived(88)

Repair of Bone Defects With Endothelial Progenitor Cells and Bone Marrow-Derived Mesenchymal Stem Cells With Tissue-Engineered Bone in Rabbits.
This study aimed to investigate the repair of bone defects in rabbits with tissue-engineered bones using cocultured endothelial progenitor cells (EPCs) and bone marrow mesenchymal stem cells (BMSCs) as seeding cells. Endothelial progenitor cells and BMSCs were isolated and purified from the peripheral blood and bone marrow, respectively, of New Zealand rabbits. The third passage of BMSCs was cultured alone or with EPCs. Cells were characterized using specific markers and then seeded on partially deproteinized biologic bones from pigs as a scaffold. The engineered bones were used to repair bone defects in rabbits. Hematoxylin and eosin and Masson staining were performed to examine vascularization and osteogenesis in the engineered bone. The cocultured EPCs and BMSCs grew well on the surface of the scaffold. Compared with monocultured BMSCs, cocultured EPCs and BMSCs promoted the formation of blood vessels and bone on the scaffold, in addition to accelerating the repair of bone defects. The collagen content was significantly increased in the scaffold with cocultured EPCs and BMSCs, compared with the scaffold seeded with mono-cultured BMSCs. Tissue-engineered bones seeded with cocultured EPCs and BMSCs may be used effectively for the repair of bone defects.
Publication Date: 2020-09-16 00:00:00
Journal: Annals of plastic surgery


Phototunable interpenetrating polymer network hydrogels to stimulate the vasculogenesis of stem cell-derived endothelial progenitors.
Vascularization of engineered scaffolds remains a critical obstacle hindering the translation of tissue engineering from the bench to the clinic. We previously demonstrated the robust micro-vascularization of collagen hydrogels with induced pluripotent stem cell (iPSC)-derived endothelial progenitors however, physically cross-linked collagen hydrogels compact rapidly and exhibit limited strength. We have synthesized an interpenetrating polymer network (IPN) hydrogel comprised of collagen and norbornene-modified hyaluronic acid (NorHA) to address these challenges. This dual-network hydrogel combines the natural cues presented by collagen's binding sites and extracellular matrix (ECM)-mimicking fibrous architecture with the in situ modularity and chemical cross-linking of NorHA. We modulated the IPN hydrogel's stiffness and degradability by varying the concentration and sequence, respectively, of the NorHA peptide cross-linker. Rheological characterization of the photo-mediated gelation process revealed that the IPN hydrogel's stiffness increased with cross-linker concentration and was decoupled from the bulk NorHA content. Conversely, the swelling of the IPN hydrogel decreased linearly with increasing cross-linker concentration. Collagen microarchitecture remained relatively unchanged across cross-linking conditions, although the addition of NorHA delayed collagen fibrillogenesis. Upon iPSC-derived endothelial progenitor encapsulation, robust, lumenized microvascular networks developed in IPN hydrogels over two weeks. Subsequent computational analysis showed that an initial rise in stiffness increased the number of branch points and vessels, but vascular growth was suppressed in high stiffness IPN hydrogels. These results suggest that an IPN hydrogel consisting of collagen and NorHA is highly tunable, compaction resistant, and capable of supporting vasculogenesis.
Publication Date: 2020-12-29 00:00:00
Journal: Acta biomaterialia


Concise review: current trends on applications of stem cells in diabetic nephropathy.
Diabetic nephropathy, with high prevalence, is the main cause of renal failure in diabetic patients. The strategies for treating DN are limited with not only high cost but an unsatisfied effect. Therefore, the effective treatment of DN needs to be explored urgently. In recent years, due to their self-renewal ability and multi-directional differentiation potential, stem cells have exerted therapeutic effects in many diseases, such as graft-versus-host disease, autoimmune diseases, pancreatic diseases, and even acute kidney injury. With the development of stem cell technology, stem cell-based regenerative medicine has been tried to be applied to the treatment of DN. Related stem cells include embryonic stem cells, induced pluripotent stem cells, mesenchymal cells, and endothelial progenitor cells. Undoubtedly, stem cell transplantation has achieved certain results in the treatment of DN animal models. However, stem cell therapy still remains certain thorny issues during treatment. For instance, poor engraftment and limited differentiation of stem cells caused by the diabetic microenvironment, differentiation into unwanted cell lineages, and malignant transformation or genetic aberrations of stem cells. At present, various researches on the therapeutic effects of stem cells in DN with different opinions are reported and the specific mechanism of stem cells is still unclear. We review here the potential mechanism of stem cells as new therapeutic agents in the treatment of DN. Also, we review recent findings and updated information about not only the utilization of stem cells on DN in both preclinical and clinical trials but limitations and future expectations of stem cell-based therapy for DN.
Publication Date: 2020-11-23 00:00:00
Journal: Cell death & disease

human endothelial progenitor(54)

[Effects of Astragaloside Ⅳ on exosome secretion and its microRNA-126 expression in human endothelial progenitor cells].
Publication Date: 2021-01-01 00:00:00
Journal: Zhonghua shao shang za zhi = Zhonghua shaoshang zazhi = Chinese journal of burns


Acute Aerobic Exercise Remodels the Adipose Tissue Progenitor Cell Phenotype in Obese Adults.
Adipose tissue pathology in obese patients often features impaired adipogenesis, angiogenesis, and chronic low-grade inflammation, all of which are regulated in large part by adipose tissue stromal vascular cells [SVC; i.e., non-adipocyte cells within adipose tissue including preadipocytes, endothelial cells (ECs), and immune cells]. Exercise is known to increase subcutaneous adipose tissue lipolysis, but the impact of exercise on SVCs in adipose tissue has not been explored. The purpose of this study was to assess the effects of a session of exercise on preadipocyte, EC, macrophage, and T cell content in human subcutaneous adipose tissue We collected abdominal subcutaneous adipose tissue samples from 10 obese adults (BMI 33 ± 3 kg/m
Publication Date: 2020-08-28 00:00:00
Journal: Frontiers in physiology


Early Cardiovascular Risk in E-cigarette Users: the Potential Role of Metals.
Electronic cigarettes (e-cigs) are a source of metals. Epidemiologic and experimental evidence support that metals are toxic to the cardiovascular system. Little is known, however, about the role that e-cig metals may play as toxicants for the possible cardiovascular effects of e-cig use. The goal of this narrative review is to summarize the evidence on e-cig use and metal exposure and on e-cig use and cardiovascular toxicity and discuss the research needs. In vitro studies show cytotoxicity and increased oxidative stress in myocardial cells and vascular endothelial cells exposed to e-liquids and e-cig aerosols, with effects partially reversed with antioxidant treatment. There is some evidence that the heating coil plays a role in cell toxicity. Mice exposed to e-cigs for several weeks showed higher levels of oxidative stress, inflammation, platelet activation, and thrombogenesis. Cross-over clinical experiments show e-cig use alters nitric oxide-mediated flow-mediated dilation, endothelial progenitor cells, and arterial stiffness. Cross-sectional evidence from large nationally representative samples in the USA support that e-cig use is associated with self-reported myocardial infarction. Smaller studies found associations of e-cig use with higher oxidized low-density protein and heart variability compared to healthy controls. Numerous studies have measured elevated levels of toxic metals in e-cig aerosols including lead, nickel, chromium, and manganese. Arsenic has been measured in some e-liquids. Several of these metals are well known to be cardiotoxic. Numerous studies show that e-cigs are a source of cardiotoxic metals. Experimental studies (in vitro, in vivo, and clinical studies) show acute toxicity of e-cigs to the vascular system. Studies of long-term toxicity in animals and humans are missing. Longitudinal studies with repeated measures of metal exposure and subclinical cardiovascular outcomes (e.g., coronary artery calcification) could contribute to determine the long-term cardiovascular effects of e-cigs and the potential role of metals in those effects.
Publication Date: 2020-11-27 00:00:00
Journal: Current environmental health reports


Exogenous bone marrow derived-putative endothelial progenitor cells attenuate ischemia reperfusion-induced vascular injury and renal fibrosis in mice dependent on pericytes.
Publication Date: 2020-11-19 00:00:00
Journal: Theranostics


One-Year COMBO Stent Outcomes in Acute Coronary Syndrome: from the COMBO Collaboration.
The COMBO biodegradable polymer sirolimus-eluting stent includes endothelial progenitor cell capture (EPC) technology for rapid endothelialization, which may offer advantage in acute coronary syndromes (ACS). We sought to analyze the performance of the COMBO stent by ACS status and ACS subtype. The COMBO collaboration (n = 3614) is a patient-level pooled dataset from the MASCOT and REMEDEE registries. We evaluated outcomes by ACS status, and ACS subtype in patients with ST segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) versus unstable angina (UA). The primary endpoint was 1-year target lesion failure (TLF), composite of cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization. Secondary outcomes included stent thrombosis (ST). We compared 1965 (54%) ACS and 1649 (46.0%) non-ACS patients. ACS presentations included 40% (n = 789) STEMI, 31% (n = 600) NSTEMI, and 29% (n = 576) UA patients. Risk of 1-year TLF was greater in ACS patients (4.5% vs. 3.3%, HR 1.51 95% CI 1.01-2.25, p = 0.045) without significant differences in definite/probable ST (1.1% vs 0.5%, HR 2.40, 95% CI 0.91-6.31, p = 0.08). One-year TLF was similar in STEMI, NSTEMI, and UA (4.8% vs 4.8% vs. 3.7%, p = 0.60), but definite/probable ST was higher in STEMI patients (1.9% vs 0.5% vs 0.7%, p = 0.03). Adjusted outcomes were not different in MI versus UA patients. Despite the novel EPC capture technology, COMBO stent PCI was associated with somewhat greater risk of 1-year TLF in ACS than in non-ACS patients, without significant differences in stent thrombosis. No differences were observed in 1-year TLF among ACS subtypes.
Publication Date: 2021-01-31 00:00:00
Journal: Cardiovascular drugs and therapy


Single-dose local intraosseous injection of simvastatin suppresses breast cancer with tumor vascular normalization.
Tumor vessels play important roles in cancer development and angiogenesis has been characterized as an essential process for tumor cell tumor growth. Our previous studies found that a single-dose local intraosseous simvastatin injection rapidly and long-termly mobilized bone marrow-derived endothelial progenitor cells to peripheral blood, promoting angiogenesis and ameliorating ischemia injury. However, whether intraosseous injection of simvastatin participates in cancer progression and the role of angiogenesis enhancement in this process remain unknown. In this study, we found that intraosseous injection of simvastatin improves tumor vascular structure, along with increasing the percentage of pericyte coverage on tumor vessels, and reducing vascular permeability, tumor hypoxia and tumor necrosis. Further, we demonstrate that a single-dose local intraosseous simvastatin injection suppresses tumor growth, facilitates sensitivity of chemotherapy and prolongs survival in breast cancer bearing mice. In addition, oral application, intravenous, subcutaneous and intraperitoneal injection of simvastatin do not show these effects. Taken together, these results demonstrate that intraosseous injection of simvastatin suppresses breast cancer with tumor vascular normalization, which might be a promising strategy for cancer treatment.
Publication Date: 2020-09-21 00:00:00
Journal: Translational oncology


Effectiveness and Safety of Extracorporeal Shockwave Myocardial Revascularization in Patients With Refractory Angina Pectoris and Heart Failure.
Extracorporeal shockwave myocardial revascularization (ESMR) is a therapy for refractory angina pectoris. Our aim was to assess the efficacy and safety of ESMR in the management of patients with stable coronary artery disease (CAD) and heart failure as well as its effects on inflammation and angiogenesis. In this single-arm prospective trial, we included 48 patients with CAD, myocardial ischemia assessed by radionuclide imaging, echocardiographic evidence of left ventricular systolic dysfunction and without revascularization options. Changes in angina grading score, myocardial perfusion, left ventricular ejection fraction, and six-minute walk test after ESMR therapy were used for efficacy assessment. Changes of inflammation and angiogenesis biomarkers were also evaluated. ESMR therapy was performed using a commercially available cardiac shockwave generator system (Cardiospec; Medispec). After 9 weeks of ESMR therapy, a significant improvement was found regarding the initial angina class, severity of ischemia, left ventricular ejection fraction, and six-minute walk test in most patients. No deleterious side effects after treatment were detected. Regarding biomarkers, endothelial progenitor cells and angiopoietin-3 were significantly increased whereas IL-18 and TGF-β were significantly decreased after ESMR in the total group. Notably, VEGF, IL-1ß, and lipoxin A4 levels were significantly increased only in patients with myocardial ischemia improvement. In conclusion, ESMR therapy is safe and effective in most but not all patients with CAD and heart failure. ESMR is associated with increased markers of angiogenesis and decreased markers of inflammation. Myocardial ischemia improvement after ESMR is associated with increased markers of angiogenesis and pro-resolving mediators.
Publication Date: 2021-01-02 00:00:00
Journal: The American journal of cardiology


Changes in Circulating Stem and Progenitor Cell Numbers Following Acute Exercise in Healthy Human Subjects: a Systematic Review and Meta-analysis.
Despite of the increasing number of investigations on the effects of acute exercise on circulating stem and progenitor cell (SC) numbers, and in particular on respective subgroups, i.e. endothelial (ESC), hematopoietic (HSC), and mesenchymal (MSC) stem and progenitor cells, a consensus regarding mechanisms and extent of these effects is still missing. The aim of this meta-analysis was to systematically evaluate the overall-effects of acute exercise on the different SC-subgroups and investigate possible subject- and intervention-dependent factors affecting the extent of SC-mobilization in healthy humans. Trials assessing SC numbers before and at least one timepoint after acute exercise, were identified in a systematic computerized search. Compared to baseline, numbers were significantly increased for early and non-specified SCs (enSCs) until up to 0.5 h after exercise (0-5 min: +0.64 [Standardized difference in means], p < 0.001; 6-20 min: +0.42, p < 0.001; 0.5 h: +0.29, p = 0.049), for ESCs until 12-48 h after exercise (0-5 min: +0.66, p < 0.001; 6-20 min: +0.43 p < 0.001; 0.5 h: +0.43, p = 0.002; 1 h: +0.58, p = 0.001; 2 h: +0.50, p = 0.002; 3-8 h: +0.70, p < 0.001; 12-48 h: +0.38, p = 0.003) and for HSCs at 0-5 min (+ 0.47, p < 0.001) and at 3 h after exercise (+ 0.68, p < 0.001). Sex, intensity and duration of the intervention had generally no influence. The extent and kinetics of the exercise-induced mobilization of SCs differ between SC-subpopulations. However, also definitions of SC-subpopulations are non-uniform. Therefore, finding a consensus with a clear definition of cell surface markers defining ESCs, HSCs and MSCs is a first prerequisite for understanding this important topic.
Publication Date: 2021-01-04 00:00:00
Journal: Stem cell reviews and reports


The secretome of endothelial progenitor cells: a potential therapeutic strategy for ischemic stroke.
Ischemic stroke continues to be a leading cause of mortality and morbidity in the world. Despite recent advances in the field of stroke medicine, thrombolysis with recombinant tissue plasminogen activator remains as the only pharmacological therapy for stroke patients. However, due to short therapeutic window (4.5 hours of stroke onset) and increased risk of hemorrhage beyond this point, each year globally less than 1% of stroke patients receive this therapy which necessitate the discovery of safe and efficacious therapeutics that can be used beyond the acute phase of stroke. Accumulating evidence indicates that endothelial progenitor cells (EPCs), equipped with an inherent capacity to migrate, proliferate and differentiate, may be one such therapeutics. However, the limited availability of EPCs in peripheral blood and early senescence of few isolated cells in culture conditions adversely affect their application as effective therapeutics. Given that much of the EPC-mediated reparative effects on neurovasculature is realized by a wide range of biologically active substances released by these cells, it is possible that EPC-secretome may serve as an important therapeutic after an ischemic stroke. In light of this assumption, this review paper firstly discusses the main constituents of EPC-secretome that may exert the beneficial effects of EPCs on neurovasculature, and then reviews the currently scant literature that focuses on its therapeutic capacity.
Publication Date: 2021-01-13 00:00:00
Journal: Neural regeneration research

pulmonary arterial hypertension(28)

Micro-RNA Analysis in Pulmonary Arterial Hypertension: Current Knowledge and Challenges.
Pulmonary arterial hypertension (PAH) is a rare, chronic disease of the pulmonary vasculature that is associated with poor outcomes. Its pathogenesis is multifactorial and includes micro-RNA (miRNA) deregulation. The understanding of the role of miRNAs in PAH is expanding quickly, and it is increasingly difficult to identify which miRNAs have the highest translational potential. This review summarizes the current knowledge of miRNA expression in PAH, discusses the challenges in miRNA analysis and interpretation, and highlights 4 promising miRNAs in this field (miR-29, miR-124, miR-140, and miR-204).
Publication Date: 2020-12-10 00:00:00
Journal: JACC. Basic to translational science


Treatment of atherosclerosis through transplantation of endothelial progenitor cells overexpressing dimethylarginine dimethylaminohydrolase (DDAH) in rabbits.
Endothelial dysfunction is a key event in the development of vascular diseases, including atherosclerosis. Endothelial progenitor cells (EPCs) play an important role in vascular repair. Decreased dimethylarginine dimethylaminohydrolase (DDAH) activity is observed in several pathological conditions, and it is associated with an increased risk of vascular disease. We hypothesized that bone marrow-derived EPCs and combination therapy with DDAH2-EPCs could reduce plaque size and ameliorate endothelial dysfunction in an atherosclerosis rabbit model. Four groups of rabbits (n = 8 per group) were subjected to a hyperlipidemic diet for a month. After establishing the atherosclerosis model, rabbits received 4 × 10 DDAH2-EPCs transplantation (p < 0.05) and EPCs transplantation (p < 0.05) were both associated with a reduction in plaque size compared to the control saline injection. The antiproliferative and antiatherogenic effects of EPCs were further enhanced by the overexpression of DDAH2 (p < 0.05, DDAH2-EPCs vs. EPCs). Furthermore, DDAH2-EPCs transplantation significantly increased endotheliual integrity compared to the EPCs transplantation Transplantation of EPCs overexpressing DDAH2 may enhance the repair of injured endothelium by reducing inflammation and restoring endothelial function. Therefore, pCMV6-mediated DDAH2 gene-transfected EPCs are a potentially valuable tool for the treatment of atherosclerosis.
Publication Date: 2021-02-04 00:00:00
Journal: International journal of cardiology

heart failure(42)

Endothelial progenitor cells mobilization after maximal exercise according to heart failure severity.
Vascular endothelial dysfunction is an underlying pathophysiological feature of chronic heart failure (CHF). Patients with CHF are characterized by impaired vasodilation and inflammation of the vascular endothelium. They also have low levels of endothelial progenitor cells (EPCs). EPCs are bone marrow derived cells involved in endothelium regeneration, homeostasis, and neovascularization. Exercise has been shown to improve vasodilation and stimulate the mobilization of EPCs in healthy people and patients with cardiovascular comorbidities. However, the effects of exercise on EPCs in different stages of CHF remain under investigation. To evaluate the effect of a symptom-limited maximal cardiopulmonary exercise testing (CPET) on EPCs in CHF patients of different severity. Forty-nine consecutive patients (41 males) with stable CHF [mean age (years): 56 ± 10, ejection fraction (EF, %): 32 ± 8, peak oxygen uptake (VO Patients with lower peak VO Our study has shown an increased EPCs and circulating endothelial cells mobilization after maximal exercise in CHF patients, but this increase was not associated with syndrome severity. Further investigation, however, is needed.
Publication Date: 2020-12-15 00:00:00
Journal: World journal of cardiology

cardiac progenitor cells(33)

Increased prostaglandin-D2 in male STAT3-deficient hearts shifts cardiac progenitor cells from endothelial to white adipocyte differentiation.
Cardiac levels of the signal transducer and activator of transcription factor-3 (STAT3) decline with age, and male but not female mice with a cardiomyocyte-specific STAT3 deficiency conditional knockout (CKO) display premature age-related heart failure associated with reduced cardiac capillary density. In the present study, isolated male and female CKO-cardiomyocytes exhibit increased prostaglandin (PG)-generating cyclooxygenase-2 (COX-2) expression. The PG-degrading hydroxyprostaglandin-dehydrogenase-15 (HPGD) expression is only reduced in male cardiomyocytes, which is associated with increased prostaglandin D2 (PGD2) secretion from isolated male but not female CKO-cardiomyocytes. Reduced HPGD expression in male cardiomyocytes derive from impaired androgen receptor (AR)-signaling due to loss of its cofactor STAT3. Elevated PGD2 secretion in males is associated with increased white adipocyte accumulation in aged male but not female hearts. Adipocyte differentiation is enhanced in isolated stem cell antigen-1 (SCA-1)+ cardiac progenitor cells (CPC) from young male CKO-mice compared with the adipocyte differentiation of male wild-type (WT)-CPC and CPC isolated from female mice. Epigenetic analysis in freshly isolated male CKO-CPC display hypermethylation in pro-angiogenic genes (Fgfr2, Epas1) and hypomethylation in the white adipocyte differentiation gene Zfp423 associated with up-regulated ZFP423 expression and a shift from endothelial to white adipocyte differentiation compared with WT-CPC. The expression of the histone-methyltransferase EZH2 is reduced in male CKO-CPC compared with male WT-CPC, whereas no differences in the EZH2 expression in female CPC were observed. Clonally expanded CPC can differentiate into endothelial cells or into adipocytes depending on the differentiation conditions. ZFP423 overexpression is sufficient to induce white adipocyte differentiation of clonal CPC. In isolated WT-CPC, PGD2 stimulation reduces the expression of EZH2, thereby up-regulating ZFP423 expression and promoting white adipocyte differentiation. The treatment of young male CKO mice with the COX inhibitor Ibuprofen or the PGD2 receptor (DP)2 receptor antagonist BAY-u 3405 in vivo increased EZH2 expression and reduced ZFP423 expression and adipocyte differentiation in CKO-CPC. Thus, cardiomyocyte STAT3 deficiency leads to age-related and sex-specific cardiac remodeling and failure in part due to sex-specific alterations in PGD2 secretion and subsequent epigenetic impairment of the differentiation potential of CPC. Causally involved is the impaired AR signaling in absence of STAT3, which reduces the expression of the PG-degrading enzyme HPGD.
Publication Date: 2020-12-29 00:00:00
Journal: PLoS biology


Cigarette smoke extract affects methylation status and attenuates Sca-1 expression of mouse endothelial progenitor cell in vitro.
Endothelial dysfunction appears in many smoking-related diseases, it is also an important pathophysiological feature. Endothelial progenitor cells (EPCs) are precursors of endothelial cells and have a crucial effect on the repair and maintenance of endothelial integrity. Sca-1 is not only common in bone marrow-derived hematopoietic stem cells (HSCs), but it is also expressed in nonhematopoietic organs by tissue-resident stem and progenitor cells. The aim of this study is to investigate the impact of cigarette smoke extract (CSE) on the function of bone marrow-derived EPCs and the expression level of Sca-1 in EPCs, and also whether the methylation of Sca-1 is involved in EPC dysfunction. We measured EPC capacities including adhesion, secretion and proliferation, the concentration of endothelial nitric oxide synthase (eNOS) and apoptosis-inducing factor (AIF) in cell culture supernatant, and also Sca-1 expression and promoter methylation in EPCs induced by CSE. Decitabine (Dec) was applied to test whether it could alter the impact caused by CSE. The adhesion, proliferation and secretion ability of EPCs can be induced to be decreased by CSE The decreased Sca-1 expression was related to EPC dysfunction induced by CSE. EPC dysfunction resulting from CSE may be related to methylation mechanism, but not the methylation of Sca-1 promoter.
Publication Date: 2021-02-06 00:00:00
Journal: Tobacco induced diseases

circulating endothelial cells(32)

Flow cytometric analysis of circulating endothelial cells and endothelial progenitor cells in pediatric solid tumors: prognostic impact on treatment response and survival.
Solid tumors, including pediatric malignancies, depend on angiogenesis for tumor growth, invasion, and metastases. We aimed to evaluate the prognostic impact of circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) on treatment response and survival of pediatric patients with solid tumors. A prospective study included 70 patients with different pediatric solid tumors treated with different types of chemotherapy and 20 age and sex-matched healthy children as controls. Blood samples collected at diagnosis then on day 7 and day 21 after chemotherapy. CECs and EPCs were evaluated using flow cytometry. The mean levels of CECs and EPCs of patients at diagnosis were significantly higher than controls (85.29 ± 24.78 and 26.1 ± 9.11 versus 20.08 ± 6.65; and EPCs; 2.78 ± 1.48, respectively; P < 0.001 for both). The highest levels of CECs were observed in patients with rhabdomyosarcoma (RMS). An overall increase was reported in CECs, and after the first cycle of chemotherapy, that was significantly correlated to treatment response and overall survival. Pediatric patients with solid tumors have elevated levels of CECs and EPCs with more elevation after chemotherapy. The magnitude of increase of CECs occurred on day 7 after chemotherapy may be considered as an early predictor of response to therapy and outcome in pediatric patients with solid tumors.
Publication Date: 2020-09-19 00:00:00
Journal: Cancer immunology, immunotherapy : CII

bone marrow-derived endothelial progenitor(30)

Phenotypic characteristics of human bone marrow-derived endothelial progenitor cells in vitro support cell effectiveness for repair of the blood-spinal cord barrier in ALS.
Amyotrophic lateral sclerosis (ALS) was recently recognized as a neurovascular disease. Accumulating evidence demonstrated blood-spinal-cord barrier (BSCB) impairment mainly via endothelial cell (EC) degeneration in ALS patients and animal models. BSCB repair may be a therapeutic approach for ALS. We showed benefits of human bone marrow endothelial progenitor cell (hBMEPC) transplantation into symptomatic ALS mice on barrier restoration; however, cellular mechanisms remain unclear. The study aimed to characterize hBMEPCs in vitro under normogenic conditions. hBMEPCs were cultured at different time points. Enzyme-linked immunosorbent assay (ELISA) was used to detect concentrations of angiogenic factors (VEGF-A, angiogenin-1, and endoglin) and angiogenic inhibitor endostatin in conditioned media. Double immunocytochemical staining for CD105, ZO-1, and occludin with F-actin was performed. Results showed predominantly gradual significant post-culture increases of VEGF-A and angiogenin-1 levels. Cultured cells displayed distinct rounded or elongated cellular morphologies and positively immunoexpressed for CD105, indicating EC phenotype. Cytoskeletal F-actin filaments were re-arranged according to cell morphologies. Immunopositive expressions for ZO-1 were detected near inner cell membrane and for occludin on cell membrane surface of adjacent hBMEPCs. Together, secretion of angiogenic factors by cultured cells provides evidence for a potential mechanism underlying endogenous EC repair in ALS through hBMEPC transplantation, leading to restored barrier integrity. Also, ZO-1 and occludin immunoexpressions, confirming hBMEPC interactions in vitro, may reflect post-transplant cell actions in vivo.
Publication Date: 2019-09-08 00:00:00
Journal: Brain research

induced pluripotent stem(38)

Multilineage differentiation potential of hematoendothelial progenitors derived from human induced pluripotent stem cells.
Human induced pluripotent stem cells (hiPSCs) offer a renewable source of cells for the generation of hematopoietic cells for cell-based therapy, disease modeling, and drug screening. However, current serum/feeder-free differentiation protocols rely on the use of various cytokines, which makes the process very costly or the generation of embryoid bodies (EBs), which are labor-intensive and can cause heterogeneity during differentiation. Here, we report a simple feeder and serum-free monolayer protocol for efficient generation of iPSC-derived multipotent hematoendothelial progenitors (HEPs), which can further differentiate into endothelial and hematopoietic cells including erythroid and T lineages. Formation of HEPs from iPSCs was initiated by inhibition of GSK3 signaling for 2 days followed by the addition of VEGF and FGF2 for 3 days. The HEPs were further induced toward mature endothelial cells (ECs) in an angiogenic condition and toward T cells by co-culturing with OP9-DL1 feeder cells. Endothelial-to-hematopoietic transition (EHT) of the HEPs was further promoted by supplementation with the TGF-β signaling inhibitor. Erythroid differentiation was performed by culturing the hematopoietic stem/progenitor cells (HSPCs) in a three-stage erythroid liquid culture system. Our protocol significantly enhanced the number of KDR This protocol offers an efficient and simple approach for the generation of multipotent HEPs and could be adapted to generate desired blood cells in large numbers for applications in basic research including developmental study, disease modeling, and drug screening as well as in regenerative medicine.
Publication Date: 2020-11-13 00:00:00
Journal: Stem cell research & therapy

type 2(58)

Expression of miR-210 in the peripheral blood of patients with newly diagnosed type 2 diabetes mellitus and its effect on the number and function of endothelial progenitor cells.
This study aims to investigate the correlation between the expression of miR-210 in peripheral blood and the number of peripheral endothelial progenitor cells (EPCs) in patients with type 2 diabetes mellitus (T2DM). We also determined the effect of miR-210 on EPC proliferation, adhesion, migration, tube formation, and apoptosis. A total of 32 patients with newly diagnosed T2DM (T2DM group) and 32 control subjects with normal glucose tolerance (NC group) were included. Peripheral blood samples were collected from each subject. The miR-210 level was determined by quantitative real-time polymerase chain reaction (qRT-PCR), and the number of positive EPCs indicated by CD34, CD133, and KDR expressions was detected by flow cytometry. After isolation, culture, and identification by fluorescent staining, EPCs were divided into four groups: NC group, untransfected type 2 diabetic group, miR-210 inhibitor NC group, and miR-210 inhibitor group. The expression of miR-120 in each group was detected by qRT-PCR, and the changes in the proliferation, adhesion, migration, tube formation, and apoptosis of EPCs after transfection with a miR-210 inhibitor were observed. The expression level of miR-210 in the T2DM group (5.83 ± 1.26) was significantly higher than that in the NC group (1.18 ± 0.54) (t = 17.26, P < 0.001). The number of EPCs was significantly lower in the T2DM group (39.3 ± 12.6)/10 The increased expression of miR-210 in patients with T2DM may be related to the decreased number and function of EPCs in peripheral blood.
Publication Date: 2020-06-14 00:00:00
Journal: Microvascular research


Circulatory Rejuvenated EPCs Derived from PAOD Patients Treated by CD34
This study tested whether circulatory endothelial progenitor cells ( EPCs derived from peripheral arterial occlusive disease (PAOD) patients after receiving combined autologous CD34+ cell and hyperbaric oxygen (HBO) therapy (defined as rejuvenated EPCs would salvage nude mouse limbs against critical limb ischemia (CLI). Adult-male nude mice (
Publication Date: 2020-10-30 00:00:00
Journal: International journal of molecular sciences


Identification of the Key Genes Involved in the Effect of Folic Acid on Endothelial Progenitor Cell Transcriptome of Patients with Type 1 Diabetes.
Type 1 diabetes (T1D) is one of the most common autoimmune diseases in children. Previous studies have suggested that endothelial progenitor cells (EPCs) might be engaged in the regulating of the biological processes in T1D and folic acid (FA) might be engaged in regulating EPC function. The present study has identified 716 downregulated genes and 617 upregulated genes in T1D EPC cases after treated with FA. Bioinformatics analysis has shown that these DEGs were engaged in regulating metabolic processes, cell proliferation-related processes, bone marrow development, cell adhesion, platelet degranulation, and cellular response to growth factor stimulus. Furthermore, we have conducted and identified hub PPI networks. Importantly, we have identified 6 upregulated genes (POLR2A, BDNF, CDC27, LTN1, RAB1A, and CUL2) and 8 downregulated genes (SHC1, GRIN2B, TTN, GNAL, GNB2, PTK2, TF, and TLR9) as key regulators involved in the effect of FA on endothelial progenitor cell transcriptome of patients with T1D. We think that this study could provide novel information to understand the roles of FA in regulating EPCs of T1D patients.
Publication Date: 2020-10-09 00:00:00
Journal: Computational and mathematical methods in medicine


Rejuvenation of Senescent Endothelial Progenitor Cells by Extracellular Vesicles Derived From Mesenchymal Stromal Cells.
Mesenchymal stromal cell (MSC) transplantation is a form of the stem-cell therapy that has shown beneficial effects for many diseases. The use of stem-cell therapy, including MSC transplantation, however, has limitations such as the tumorigenic potential of stem cells and the lack of efficacy of aged autologous cells. An ideal therapeutic approach would keep the beneficial effects of MSC transplantation while circumventing the limitations associated with the use of intact stem cells. This study provides proof-of-concept evidence that MSC- derived extracellular vesicles represent a promising platform to develop an acellular therapeutic approach that would just do that. Extracellular vesicles are membranous vesicles secreted by MSCs and contain bioactive molecules to mediate communication between different cells. Extracellular vesicles can be taken up by recipient cells, and once inside the recipient cells, the bioactive molecules are released to exert the beneficial effects on the recipient cells. This study, for the first time to our knowledge, shows that extracellular vesicles secreted by MSCs recapitulate the beneficial effects of MSCs on vascular repair and promote blood vessel regeneration after ischemic events. Furthermore, MSCs from aged donors can be engineered to produce extracellular vesicles with improved regenerative potential, comparable to MSCs from young donors, thus eliminating the need for allogenic young donors for elderly patients.
Publication Date: 2020-12-10 00:00:00
Journal: JACC. Basic to translational science

embryonic stem cells(25)

Definitive hematopoietic stem/progenitor cells from human embryonic stem cells through serum/feeder-free organoid-induced differentiation.
Ex vivo production of hematopoietic stem/precursor cells (HSPCs) represents a promising versatile approach for blood disorders. To derive definitive HSPCs from human embryonic stem cells (ESCs), we differentiated mesodermally specified embryoid bodies (EBs) on gelatin-coated plates in serum/feeder-free conditions. Seven-day EB maturation followed by an 8-day differentiation period on OP9 cells provided the highest number of definitive (CD34+ CD235a-, 69%, p < 0.01) and lowest number of primitive (CD34- CD235a+, 1.55%, p < 0.01) precursor cells along with the highest colony-forming units (149.8 ± 11.6, p < 0.01) in feeder-free conditions. Maximal HSPC fraction (CD34+ CD38- CD45RA- CD49f+ CD90+) was 7.6-8.9% after 10 days of hematopoietic differentiation with 14.5% adult β-globin expression following RBC differentiation. Myeloid and erythroid colonies were restricted strictly to the CD34+ CD43+ fraction (370.5 ± 65.7, p < 0.001), while the CD34- CD43+ fraction produced only a small number of colonies (21.6 ± 11.9). In addition, we differentiated the CD34+ CD43+ cells towards T-lymphocytes using the OP9/DLL1 co-culture system demonstrating double-positive T cells (CD4+ CD8+) with CD3+ expression displaying a broad T cell receptor (TCR) repertoire. Confocal imaging of organoid-like structures revealed a close association of CD31+ cells with CD34+ and CD43+ cells, suggesting a potential emergence of HSPCs through endothelial to hematopoietic transition. Furthermore, fluorescently labeled organoids exhibited the emergence of spherical non-attached cells from rare progenitors at the border of the organoid center. In summary, definitive HSPCs can be derived from ESCs through a dynamic cellular process from an organoid-like structure, where erythroid progeny are capable of producing adult hemoglobin and lymphoid progeny shows a diverse TCR repertoire.
Publication Date: 2020-11-26 00:00:00
Journal: Stem cell research & therapy


A new method of culturing rat bone marrow endothelial progenitor cells
Endothelial progenitor cells (EPCs) play an important role in the re-endothelialization of ischemic cerebrovascular disease. However, the current acquisition method has some deficiencies. This study aimed to design a new and practical method for obtaining EPCs. Bone marrow was obtained autologously from the right tibia of living rat . Briefly, the right tibia bone was carefully exposed and two holes (1 mm in diameter) were made in the tuberosity and lower one-third of the tibia, respectively. A PE-50 catheter and syringe (5 mL) were inserted through the holes to aspi rat the bone marrow. Bone marrow mononuclear cells (BMMCs) were isolated by density-gradient centrifugation with Ficoll and counted. Adherent cell culture continued for 2 weeks, and the medium was replaced every 3 days. During the first days of culture, adherent cells formed a monolayer, consisting predominantly of small-sized cells. Single large cells with endothelial morphology were observed. On day 4, the nonadherent cells were removed, and the adherent cells were left for further culture. On day 6-7, a prolife rat ng population of round cells formed clusters in the culture chamber, and morphological analysis revealed a homogeneous population of colony-forming units (CFUs). Large, flat cells with endothelial morphology sprouted from the CFUs, which had nearly disappeared by day 14 of culture. The adherent cells were positive for CD133 and vascular endothelial growth factor receptor 2 (VEGFR2), internalized acetylated low-density lipoprotein, and bound ulex europaeus-agglutinin-I, but were negative for CD45, which correlated with the endothelial morphology and ability to form capillaries of EPCs. Our results are direct evidence that mononuclear cells (MCS) from living rat bone marrow can be used to culture EPCs
Publication Date: 2020-11-24 00:00:00
Journal: Cardiovascular diagnosis and therapy

circulating progenitor cells(28)

Altered kinetics of circulating progenitor cells in cardiopulmonary bypass (CPB) associated vasoplegic patients: A pilot study.
Vasoplegia observed post cardiopulmonary bypass (CPB) is associated with substantial morbidity, multiple organ failure and mortality. Circulating counts of hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPC) are potential markers of neo-vascularization and vascular repair. However, the significance of changes in the circulating levels of these progenitors in perioperative CPB, and their association with post-CPB vasoplegia, are currently unexplored. We enumerated HSC and EPC counts, via flow cytometry, at different time-points during CPB in 19 individuals who underwent elective cardiac surgery. These 19 individuals were categorized into two groups based on severity of post-operative vasoplegia, a clinically insignificant vasoplegic Group 1 (G1) and a clinically significant vasoplegic Group 2 (G2). Differential changes in progenitor cell counts during different stages of surgery were compared across these two groups. Machine-learning classifiers (logistic regression and gradient boosting) were employed to determine if differential changes in progenitor counts could aid the classification of individuals into these groups. Enumerating progenitor cells revealed an early and significant increase in the circulating counts of CD34+ and CD34+CD133+ hematopoietic stem cells (HSC) in G1 individuals, while these counts were attenuated in G2 individuals. Additionally, EPCs (CD34+VEGFR2+) were lower in G2 individuals compared to G1. Gradient boosting outperformed logistic regression in assessing the vasoplegia grouping based on the fold change in circulating CD 34+ levels. Our findings indicate that a lack of early response of CD34+ cells and CD34+CD133+ HSCs might serve as an early marker for development of clinically significant vasoplegia after CPB.
Publication Date: 2020-11-20 00:00:00
Journal: PloS one


Effects of switching from clopidogrel to prasugrel at the chronic phase after coronary stenting on antiplatelet action and vascular endothelial function: Switch-Pras study.
Compared to clopidogrel, prasugrel has a lower incidence of ischemic events following percutaneous coronary intervention (PCI) because of an early reduction during the acute phase in P2Y12 reaction units (PRU). The objective of this study was to compare the antiplatelet effect and vascular endothelial function of both drugs during the chronic phase after PCI. Patients who had undergone PCI and were confirmed to have no restenosis by follow-up coronary angiography under dual anti-platelet therapy with clopidogrel (75 mg/day) and aspirin (100 mg/day) were randomized to either continue clopidogrel or switch to prasugrel (3.75 mg/day). At baseline, prior to randomization we determined the CYP2C19 genotype. At the baseline and 24 weeks after randomization, the P2Y12 reactivity unit (PRU) was measured using the VerifyNow™ P2Y12 assay. Endothelial function was evaluated by flow-mediated vasodilation (FMD) and reactive hyperemia peripheral arterial tonometry (RH-PAT), while and circulating CD34+/CD133+/CD45
Publication Date: 2020-10-29 00:00:00
Journal: Heart and vessels


A 2020 View of Thymus Stromal Cells in T Cell Development.
The thymus is an intricate primary lymphoid organ, wherein bone marrow-derived lymphoid progenitor cells are induced to develop into functionally competent T cells that express a diverse TCR repertoire, which is selected to allow for the recognition of foreign Ags while avoiding self-reactivity or autoimmunity. Thymus stromal cells, which can include all non-T lineage cells, such as thymic epithelial cells, endothelial cells, mesenchymal/fibroblast cells, dendritic cells, and B cells, provide signals that are essential for thymocyte development as well as for the homeostasis of the thymic stroma itself. In this brief review, we focus on the key roles played by thymic stromal cells during early stages of T cell development, such as promoting the homing of thymic-seeding progenitors, inducing T lineage differentiation, and supporting thymocyte survival and proliferation. We also discuss recent advances on the transcriptional regulation that govern thymic epithelial cell function as well as the cellular and molecular changes that are associated with thymic involution and regeneration.
Publication Date: 2021-01-06 00:00:00
Journal: Journal of immunology (Baltimore, Md. : 1950)

hematopoietic stem cell(34)

Multifaceted Actions of GFI1 and GFI1B in Hematopoietic Stem Cell Self-Renewal and Lineage Commitment.
Growth factor independence 1 (GFI1) and the closely related protein GFI1B are small nuclear proteins that act as DNA binding transcriptional repressors. Both recognize the same consensus DNA binding motif
Publication Date: 2020-11-17 00:00:00
Journal: Frontiers in genetics


Correction to: Plaque Regression and Endothelial Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER).
Publication Date: 2020-10-21 00:00:00
Journal: Circulation. Cardiovascular interventions


Genetic Factors as the Basis of Sex Differences in Damage to Lung Endothelium and Regulation of Angiogenesis Cells in Modeling Pulmonary Emphysema in C57BL/6 Mice with Dyslipidemia and Hyperglycemia.
We studied the formation of injuries in lung endothelium and the response of angiogenesis cells during modeling of pulmonary emphysema in male and female C57BL/6 mice with metabolic disorders. Hemodynamic disturbances and reduction in the area of the microvasculature caused by combined pathology in male mice were more pronounced than in females. Mobilization and migration of angiogenic precursors were impaired in both male and female mice. In males, activity of recruiting endothelial progenitor cells, vascular smooth muscle cells, luminal cells of nascent vessels and pericytes into the lung was additionally reduced. In females, accumulation of endothelial progenitor cells (CD45
Publication Date: 2021-01-17 00:00:00
Journal: Bulletin of experimental biology and medicine


Pro-inflammatory Mediators and Oxidative Stress: Therapeutic Markers for Recurrent Angina Pectoris after Coronary Artery Stenting in Elderly Patients.
Pro-inflammatory mediators and oxidative stress are related to severity of angina pectoris in patients with coronary heart disease. We evaluated the effects of pro-inflammatory mediators and oxidative stress on recurrent angina pectoris after coronary artery stenting in elderly patients. We determined the expression levels of malondialdehyde (MDA), acrolein (ACR), tumour necrosis factor-α (TNF-α), toll-like receptor 4 (TLR4), superoxide dismutase 3 (SOD3), paraoxonase-1 (PON-1), stromal cell-derived factor-1α (SDF-1α) and endothelial progenitor cells (EPCs) in elderly patients with recurrent angina pectoris after coronary artery stenting. Levels of MDA, ACR, TNF-α and TLR4 were significantly increased (p<0.001), and levels of SOD3, PON-1, SDF-1α and EPCs were significantly decreased (p<0.001) in the elderly patients with recurrent angina pectoris after coronary artery stenting. MDA, ACR, TNF-α and TLR4 as markers of oxidative stress and pro-inflammatory mediators may have suppressed SOD3, PON-1, SDF-1α and EPCs as markers of anti-oxidative stress anti-inflammatory responses. Oxidative stress and pro-inflammatory mediators were important factors involved in recurrent angina pectoris of elderly patients after coronary artery stenting. Oxidative stress and pro-inflammatory mediators could be considered as potential non-invasive prognostic, predictive and therapeutic biomarkers for stable recurrent angina and recurrent unstable angina in the elderly patients after coronary artery stenting.
Publication Date: 2021-01-30 00:00:00
Journal: Current vascular pharmacology

type 1 diabetes(18)

Effects of glucose variability on hematopoietic stem/progenitor cells in patients with type 1 diabetes.
Diabetes reduces the levels of hematopoietic stem/progenitor cells (HSPCs), which can contribute to organ and tissue homeostasis. Among patients with diabetes, lower HSPC levels predict the development or worsening of micro- and macro-angiopathy. High glucose variability is also associated with diabetic complications and we have previously shown that acute hypoglycaemia can stimulate stem/progenitor cells. Thus, we evaluated the relationship between glucose variability or time in hypoglycaemia and HSPCs in patients with type 1 diabetes (T1D). Patients with T1D were compared to healthy subjects. HSPCs (CD34 Forty-four patients with T1D and 44 healthy subjects were enrolled. Compared to healthy controls, T1D patients had significantly lower levels of HSPCs and duration of diabetes was inversely correlated with HSPC levels. Significant direct correlations were found between HSPC levels and the coefficient of variation of glucose levels or time in hypoglycaemia, which were stronger in patients with short-term than in those with long-standing diabetes. This study confirms the pauperization of HSPCs in T1D patients and demonstrates a potential HSPC-stimulatory effect of hypoglycaemia, which mitigates with long-lasting diabetes. These data are consistent with a model whereby disease chronicity progressively blunts the release of HSPCs in response to adrenergic triggers, like hypoglycaemic events.
Publication Date: 2020-05-06 00:00:00
Journal: Journal of endocrinological investigation

cells epcs(12)

Increased circulating endothelial progenitor cells (EPCs) in prepubertal children born prematurely: a possible link between prematurity and cardiovascular risk.
Endothelial progenitor cells (EPCs) ensure vascular integrity and neovascularization. No studies have investigated EPCs in preterm-born children beyond infancy. One hundred and thirty-six prepubertal children were enrolled: 63 preterm and 73 born at term (controls). Circulating CD34(+)/VEGFR-2(+)/CD45(-) and CD34(+)/VEGFR-2(+)/CD45dim EPCs were measured in preterm-born children compared to controls. Body mass index (BMI), waist-to-hip ratio (WHR), neck circumference, systolic and diastolic blood pressure (SBP and DBP, respectively), fasting glucose, insulin, lipid profile, common carotid and abdominal aortic intima-media thickness (cIMT and aIMT, respectively), endothelium-dependent brachial artery flow-mediated dilation (FMD), and echocardiographic parameters were also assessed. Circulating CD34(+)/VEGFR-2(+)/CD45(-) and CD34(+)/VEGFR-2(+)/CD45dim EPCs were significantly higher in preterm-born children compared to controls (p < 0.001 and p < 0.001, respectively). In total study population and in the preterm-born group, EPCs were significantly lower in children born to mothers with gestational diabetes compared to non-diabetic mothers. Prematurity was associated with higher WHR, neck circumference, SBP, DBP, cIMT, aIMT, mean pressure, and velocity of pulmonary artery; the peak velocity of the brachial artery was significantly lower in children born prematurely. In multiple regression analysis, preterm birth and maternal gestational diabetes were recognized as independent predictors of EPCs. Circulating EPCs were increased in prepubertal preterm-born children in comparison with peers born full-term. Maternal gestational diabetes was associated with a decrease in EPCs. Mounting evidence supports the adverse effect of prematurity on cardiovascular health. However, the underlying mechanisms that could lead to endothelial dysfunction in preterm-born individuals are not fully understood. Endothelial progenitor cells (EPCs) ensure vascular integrity, normal endothelial function and neovascularization. No studies have investigated the EPCs counts in peripheral blood beyond infancy in children born prematurely. Circulating EPCs were significantly higher in preterm-born prepubertal children compared to controls, thus indicating that prematurity is possibly associated with endothelial damage. In total study population and in the preterm-born group, maternal gestational diabetes was associated with decreased EPCs concentrations.
Publication Date: 2020-10-11 00:00:00
Journal: Pediatric research


Sustained neuronal viability by paracrine factors: new opportunities for endothelial progenitor cell secretome.
Publication Date: 2020-12-16 00:00:00
Journal: Neural regeneration research

colony forming cells(24)

Cord blood-endothelial colony forming cells are immunotolerated and participate at post-ischemic angiogenesis in an original dorsal chamber immunocompetent mouse model.
Cardiovascular diseases are the main cause of morbidity and mortality worldwide. Restoring blood supply to ischemic tissues is an essential goal for the successful treatment of these diseases. Growth factor or gene therapy efficacy remains controversial, but stem cell transplantation is emerging as an interesting approach to stimulate angiogenesis. Among the different stem cell populations, cord blood-endothelial progenitor cells (CB-EPCs) and more particularly cord blood-endothelial progenitor cell-derived endothelial colony forming cells (CB-ECFCs) have a great proliferative potential without exhibiting signs of senescence. Even if it was already described that CB-ECFCs were able to restore blood perfusion in hind-limb ischemia in an immunodeficient mouse model, until now, the immunogenic potential of allogenic CB-ECFCs remains controversial. Therefore, our objectives were to evaluate the immune tolerance potency of CB-ECFCs and their capacity to restore a functional vascular network under ischemic condition in immunocompetent mice. In vitro, the expression and secretion of immunoregulatory markers (HLA-G, IL-10, and TGF-β1) were evaluated on CB-ECFCs. Moreover, CB-ECFCs were co-cultured with activated peripheral blood mononuclear cells (PBMCs) for 6 days. PBMC proliferation was evaluated by [3H]-thymidine incorporation on the last 18 h. In vivo, CB-ECFCs were administered in the spleen and muscle of immunocompetent mice. Tissues were collected at day 14 after surgery. Finally, CB-ECFCs were injected intradermally in C57BL/6JRj mice close to ischemic macrovessel induced by thermal cauterization. Mice recovered until day 5 and were imaged, twice a week until day 30. Firstly, we demonstrated that CB-ECFCs expressed HLA-G, IL-10, and TGF-β1 and secreted IL-10 and TGF-β1 and that they could display immunosuppressive properties in vitro. Secondly, we showed that CB-ECFCs could be tolerated until 14 days in immunocompetent mice. Thirdly, we revealed in an original ischemic model of dorsal chamber that CB-ECFCs were integrated in a new functional vascular network. These results open up new perspectives about using CB-ECFCs as an allogeneic cell therapy product and gives new impulse to the treatment of cardiovascular diseases.
Publication Date: 2020-05-10 00:00:00
Journal: Stem cell research & therapy


TNFα priming through its interaction with TNFR2 enhances endothelial progenitor cell immunosuppressive effect: new hope for their widespread clinical application.
Bone marrow derived endothelial progenitor cells (EPCs) are immature endothelial cells (ECs) involved in neo-angiogenesis and endothelial homeostasis and are considered as a circulating reservoir for endothelial repair. Many studies showed that EPCs from patients with cardiovascular pathologies are impaired and insufficient; hence, allogenic sources of EPCs from adult or cord blood are considered as good choices for cell therapy applications. However, allogenic condition increases the chance of immune rejection, especially by T cells, before exerting the desired regenerative functions. TNFα is one of the main mediators of EPC activation that recognizes two distinct receptors, TNFR1 and TNFR2. We have recently reported that human EPCs are immunosuppressive and this effect was TNFα-TNFR2 dependent. Here, we aimed to investigate if an adequate TNFα pre-conditioning could increase TNFR2 expression and prime EPCs towards more immunoregulatory functions. EPCs were pre-treated with several doses of TNFα to find the proper dose to up-regulate TNFR2 while keeping the TNFR1 expression stable. Then, co-cultures of human EPCs and human T cells were performed to assess whether TNFα priming would increase EPC immunosuppressive and immunomodulatory effect. Treating EPCs with 1 ng/ml TNFα significantly up-regulated TNFR2 expression without unrestrained increase of TNFR1 and other endothelial injury markers. Moreover, TNFα priming through its interaction with TNFR2 remarkably enhanced EPC immunosuppressive and anti-inflammatory effects. Conversely, blocking TNFR2 using anti-TNFR2 mAb followed by 1 ng/ml of TNFα treatment led to the TNFα-TNFR1 interaction and polarized EPCs towards pro-inflammatory and immunogenic functions. We report for the first time the crucial impact of inflammation notably the TNFα-TNFR signaling pathway on EPC immunological function. Our work unveils the pro-inflammatory role of the TNFα-TNFR1 axis and, inversely the anti-inflammatory implication of the TNFα-TNFR2 axis in EPC immunoregulatory functions. Priming EPCs with 1 ng/ml of TNFα prior to their administration could boost them toward a more immunosuppressive phenotype. This could potentially lead to EPCs' longer presence in vivo after their allogenic administration resulting in their better contribution to angiogenesis and vascular regeneration. Video Abstract.
Publication Date: 2021-01-06 00:00:00
Journal: Cell communication and signaling : CCS

cord blood(39)

Arterial endothelium creates a permissive niche for expansion of human cord blood hematopoietic stem and progenitor cells.
Although cord blood (CB) offers promise for treatment of patients with high-risk hematological malignancies and immune disorders, the limited numbers of hematopoietic stem cell (HSC)/progenitor cell in a CB unit and straitened circumstances in expanding ex vivo make it quite challenging to develop the successful cell therapies. In this study, a novel strategy has been developed to support ex vivo expansion of hematopoietic stem and progenitor cells (HSPCs) by coculture with engineered human umbilical arterial endothelial cells (HuAECs-E4orf1-GFP), which expresses E4ORF1 stably by using a retroviral system. Coculture of CD34 Collectively, we demonstrated that HuAECs acted as a permissive niche in facilitating expansion of HSPCs. Our study further implicated that the crucial factors and related pathways presented in HuAECs may give a hint to maintain self-renewal of bona fide HSCs.
Publication Date: 2020-08-18 00:00:00
Journal: Stem cell research & therapy

stem cell-derived(45)

Intravenously Injected Pluripotent Stem Cell-derived Cells Form Fetomaternal Vasculature and Prevent Miscarriage in Mouse.
Miscarriage is the most common complication of pregnancy, and about 1% of pregnant women suffer a recurrence. Using a widely used mouse miscarriage model, we previously showed that intravenous injection of bone marrow (BM)-derived endothelial progenitor cells (EPCs) may prevent miscarriage. However, preparing enough BM-derived EPCs to treat a patient might be problematic. Here, we demonstrated the generation of mouse pluripotent stem cells (PSCs), propagation of sufficient PSC-derived cells with endothelial potential (PSC-EPs), and intravenous injection of the PSC-EPs into the mouse miscarriage model. We found that the injection prevented miscarriage. Three-dimensional reconstruction images of the decidua after tissue cleaning revealed robust fetomaternal neovascularization induced by the PSC-EP injection. Additionally, the injected PSC-EPs directly formed spiral arteries. These findings suggest that intravenous injection of PSC-EPs could become a promising remedy for recurrent miscarriage.
Publication Date: 2020-12-23 00:00:00
Journal: Cell transplantation


Efficacy and biomarker analysis of CD133-directed CAR T cells in advanced hepatocellular carcinoma: a single-arm, open-label, phase II trial.
Expressed by cancer stem cells of various epithelial cell origins and hepatocellular carcinoma (HCC), CD133 is an attractive therapeutic target for HCC. The marker CD133 is highly expressed in endothelial progenitor cells (EPC). EPCs circulate in increased numbers in the peripheral blood of patients with highly vascularized HCC and contribute to angiogenesis and neovascularization. This phase II study investigated CD133-directed chimeric antigen receptor (CAR) T (CART-133) cells in adults with HCC. Patients with histologically confirmed and measurable advanced HCC and adequate hematologic, hepatic, and renal functions received CART-133 cell infusions. The primary endpoints were safety in phase I and progression-free survival (PFS) and overall survival (OS) in phase II. Other endpoints included biomarkers for CART-133 T cell therapy. Between June 1, 2015, and September 1, 2017, this study enrolled 21 patients who subsequently received CART-133 T cells across phases I and II. The median OS was 12 months (95% CI, 9.3-15.3 months) and the median PFS was 6.8 months (95% CI, 4.3-8.4 months). Of 21 evaluable patients, 1 had a partial response, 14 had stable disease for 2 to 16.3 months, and 6 progressed after T-cell infusion. The most common high-grade adverse event was hyperbilirubinemia. Outcome was correlated with the baseline levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor 2 (sVEGFR2), stromal cell-derived factor (SDF)-1, and EPC counts. Changes in EPC counts, VEGF, SDF-1, sVEGFR2, and interferon (IFN)-γ after cell infusion were associated with survival. In patients with previously treated advanced HCC, CART-133 cell therapy demonstrates promising antitumor activity and a manageable safety profile. We identified early changes in circulating molecules as potential biomarkers of response to CART-133 cells. The predictive value of these proangiogenic and inflammatory factors as potential biomarkers of CART-133 cell therapy in HCC will be explored in prospective trial . This study is registered at Clinical Trial .gov (NCT02541370).
Publication Date: 2020-12-15 00:00:00
Journal: Oncoimmunology


Constitutive Atg5 overexpression in mouse bone marrow endothelial progenitor cells improves experimental acute kidney injury.
Endothelial Progenitor Cells have been shown as effective tool in experimental AKI. Several pharmacological strategies for improving EPC-mediated AKI protection were identified in recent years. Aim of the current study was to analyze consequences of constitutive Atg5 activation in murine EPCs, utilized for AKI therapy. Ischemic AKI was induced in male C57/Bl6N mice. Cultured murine EPCs were systemically injected post-ischemia, either natively or after Atg5 transfection (Adenovirus-based approach). Mice were analyzed 48 h and 6 weeks later. Both, native and transfected EPCs (EPCs Constitutive Atg5 activation augments AKI-protective effects of murine EPCs. The exact clinical consequences need to be determined.
Publication Date: 2020-11-25 00:00:00
Journal: BMC nephrology

adipose-derived stem cells(24)

Adipose-derived stem cells promote diabetic wound healing via the recruitment and differentiation of endothelial progenitor cells into endothelial cells mediated by the VEGF-PLCγ-ERK pathway.
Adipose-derived stem cell (ADSC) therapy is a promising treatment strategy for wound healing; however, the mechanism underlying this effect remains unclear. In the present study, we aimed to explore the influence of ADSC-derived VEGF on diabetic wounds and its role in modulating endothelial progenitor cells. The effect of ADSCs and ADSC-derived VEGF in vivo was investigated using a diabetic wound healing model, and inflammatory factors, such as IL-6, IL-10, and TNF-α, were detected. RT-qPCR and western blot analysis were used to detect the expression of downstream targets. In addition, the role of ADSC-derived VEGF in modulating endothelial progenitor cells (EPCs) was investigated using EdU assay, CD-31 immunofluorescence, and Transwell assay in vitro. The results show that ADSCs accelerated diabetic wound tissue closure and decreased the expression of inflammatory factors, such as IL-6, IL-10, and TNF-α. Further molecular mechanism studies indicated that coculturing EPCs with ADSC--conditioned medium enhanced the proliferation, mobilization and differentiation of EPCs into endothelial cells. This enhancement was inhibited when the expression of the VEGF downstream signal molecules VEGFR2, PLCγ, and ERK1/ERK2 was blocked, indicating that ADSCs might accelerate diabetic wound healing through the recruitment and differentiation of EPCs mediated by VEGF. Overall, the results of the study revealed that ADSCs could promote diabetic wound healing through the recruitment and differentiation of EPCs via angiogenesis effects regulated by the VEGF-PLCγ-ERK1/ERK2 pathway and suppression of the inflammatory response. In addition, it will be helpful to establish further understanding of ADSC therapy for clinical application.
Publication Date: 2020-08-04 00:00:00
Journal: Archives of biochemistry and biophysics


Multipotent adult progenitor cells grown under xenobiotic-free conditions support vascularization during wound healing.
Cell therapy has been evaluated pre-clinically and clinically as a means to improve wound vascularization and healing. While translation of this approach to clinical practice ideally requires the availability of clinical grade xenobiotic-free cell preparations, studies proving the pre-clinical efficacy of the latter are mostly lacking. Here, the potential of xenobiotic-free human multipotent adult progenitor cell (XF-hMAPC®) preparations to promote vascularization was evaluated. The potential of XF-hMAPC cells to support blood vessel formation was first scored in an in vivo Matrigel assay in mice. Next, a dose-response study was performed with XF-hMAPC cells in which they were tested for their ability to support vascularization and (epi) dermal healing in a physiologically relevant splinted wound mouse model. XF-hMAPC cells supported blood vessel formation in Matrigel by promoting the formation of mature (smooth muscle cell-coated) vessels. Furthermore, XF-hMAPC cells dose-dependently improved wound vascularization associated with increasing wound closure and re-epithelialization, granulation tissue formation, and dermal collagen organization. Here, we demonstrated that the administration of clinical-grade XF-hMAPC cells in mice represents an effective approach for improving wound vascularization and healing that is readily applicable for translation in humans.
Publication Date: 2020-09-08 00:00:00
Journal: Stem cell research & therapy


Conditioned media from endothelial progenitor cells cultured in simulated microgravity promote angiogenesis and bone fracture healing.
Paracrine signaling from endothelial progenitor cells (EPCs) is beneficial for angiogenesis and thus promote tissue regeneration. Microgravity (MG) environment is found to facilitate the functional potentials of various stem or progenitor cells. The present study aimed to elucidate the effects of MG on pro-angiogenic properties and fracture repair capacities of conditioned media (CM) from EPCs. Human peripheral blood-derived EPCs were cultured under MG or normal gravity (NG) followed by analysis for angiogenic gene expression. Furthermore, the serum-free CM under MG (MG-CM) or NG (NG-CM) were collected, and their pro-angiogenic properties were examined in human umbilical vein endothelial cells (HUVECs). In order to investigate the effects of MG-CM on fracture healing, they were injected into the fracture gaps of rat models, and radiography, histology, and mechanical test were performed to evaluate neovascularization and fracture healing outcomes. MG upregulated the expression of hypoxia-induced factor-1α (HIF-1α) and endothelial nitric oxide synthase (eNOS) and promote NO release. Comparing to NG-CM, MG-CM significantly facilitated the proliferation, migration, and angiogenesis of HUVECs through NO-induced activation of FAK/Erk1/2-MAPK signaling pathway. In addition, MG-CM were verified to improve angiogenic activities in fracture area in a rat tibial fracture model, accelerate fracture healing, and well restore the biomechanical properties of fracture bone superior to NG-CM. These findings provided insight into the use of MG bioreactor to enhance the angiogenic properties of EPCs' paracrine signals via HIF-1α/eNOS/NO axis, and the administration of MG-CM favored bone fracture repair.
Publication Date: 2021-01-10 00:00:00
Journal: Stem cell research & therapy


Induced expression of P-gp and BCRP transporters on brain endothelial cells using transferrin functionalized nanostructured lipid carriers: A first step of a potential strategy for the treatment of Alzheimer's disease.
P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are two transporters expressed in human neural stem/progenitor cells and at the Blood- Brain Barrier (BBB) level with decreased activity in the early stage of Alzheimer's disease (AD). Both proteins, have a protective role for the embryonic stem cells in the early developmental step, maintaining them in an undifferentiated state, and limit the access of exogenous and endogenous agents to the brain Recently, MC111 selected from a P-gp/BCRP ligands library was investigated as multitarget strategy for AD treatment, considering its ability to induce the expression and activity of both proteins. However, MC111 clinical use could be limited for the ubiquitous physiological expression of efflux transporters and its moderate toxicity towards endothelial cells. Therefore, a selective MC111 delivery system based on nanostructured lipid carriers (NLC) functionalized with transferrin were developed. The results proved the formation of NLC with average size about 120 nm and high drug encapsulation efficiency (EE% greater than 50). In vitro studies on hCMEC/D3 cells revealed that the MC111 was selectively released by NLC at BBB level and then inducing the activity and expression of BCRP and P-gp, involved in the clearance of amyloid β peptide on brain endothelial cells.
Publication Date: 2020-10-30 00:00:00
Journal: International journal of pharmaceutics

diabetic mice(25)

Procyanidin B2 improves endothelial progenitor cell function and promotes wound healing in diabetic mice via activating Nrf2.
One of the major reasons for the delayed wound healing in diabetes is the dysfunction of endothelial progenitor cells (EPCs) induced by hyperglycaemia. Improvement of EPC function may be a potential strategy for accelerating wound healing in diabetes. Procyanidin B2 (PCB2) is one of the major components of procyanidins, which exhibits a variety of potent pharmacological activities. However, the effects of PCB2 on EPC function and diabetic wound repair remain elusive. We evaluated the protective effects of PCB2 in EPCs with high glucose (HG) treatment and in a diabetic wound healing model. EPCs derived from human umbilical cord blood were treated with HG. The results showed that PCB2 significantly preserved the angiogenic function, survival and migration abilities of EPCs with HG treatment, and attenuated HG-induced oxidative stress of EPCs by scavenging excessive reactive oxygen species (ROS). A mechanistic study found the protective role of PCB2 is dependent on activating nuclear factor erythroid 2-related factor 2 (Nrf2). PCB2 increased the expression of Nrf2 and its downstream antioxidant genes to attenuate the oxidative stress induced by HG in EPCs, which were abolished by knockdown of Nrf2 expression. An in vivo study showed that intraperitoneal administration of PCB2 promoted wound healing and angiogenesis in diabetic mice which was accompanied by a significant reduction in ROS level and an increase in circulating EPC number. Taken together, our results indicate that PCB2 treatment accelerates wound healing and increases angiogenesis in diabetic mice which may be mediated by improving the mobilization and function of EPCs.
Publication Date: 2020-11-21 00:00:00
Journal: Journal of cellular and molecular medicine

progenitor cell mobilization(24)

Plaque Regression and Endothelial Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER).
Low-density lipoproteins (LDLs) are removed by extracorporeal filtration during LDL apheresis. It is mainly used in familial hyperlipidemia. The PREMIER trial (Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen) evaluated LDL apheresis in nonfamilial hyperlipidemia acute coronary syndrome patients treated with percutaneous coronary intervention. We randomized 160 acute coronary syndrome patients at 4 Veterans Affairs centers within 72 hours of percutaneous coronary intervention to intensive lipid-lowering therapy (ILLT) comprising single LDL apheresis and statins versus standard medical therapy (SMT) with no LDL apheresis and statin therapy alone. Trial objectives constituted primary safety and primary efficacy end points and endothelial progenitor cell colony-forming unit mobilization in peripheral blood. Mean LDL reduction at discharge was 53% in ILLT and 17% in SMT groups ( PREMIER is the first randomized clinical trial to demonstrate safety and a trend for early coronary plaque regression with LDL apheresis in nonfamilial hyperlipidemia acute coronary syndrome patients treated with percutaneous coronary intervention. Registration: URL: Unique identifier: NCT01004406 and NCT02347098.
Publication Date: 2020-08-15 00:00:00
Journal: Circulation. Cardiovascular interventions

late endothelial progenitor cells(20)

Importance of β2AR elevation for re-endothelialization capacity mediated by late endothelial progenitor cells in hypertensive patients.
Dysfunction of late endothelial progenitor cells (EPCs) has been suggested to be associated with hypertension. β2 adrenergic receptor (β2AR) is a novel and key target for EPCs homing. Here, we proposed that attenuated β2AR signaling contributes to EPCs dysfunction, whereas enhanced β2AR signaling restores EPCs' functions in hypertension. EPCs derived from hypertensive patients exhibited reduced cell number, impaired in vitro migratory and adhesion abilities, and impaired re-endothelialization after transplantation in nude mice with carotid artery injury. β2AR expression of EPCs from hypertensive patients was markedly downregulated, whereas the phosphorylation of the p38 mitogen-activated protein kinase (p38-MAPK) was elevated. The cleaved caspase-3 levels were elevated in EPCs. The overexpression of β2AR in EPCs from hypertensive patients inhibited p38-MAPK signaling while enhanced in vitro EPC proliferation, migration and adhesion, and in vivo re-endothelialization. The β2AR-mediated effects were attenuated by treating the EPCs with a neutralizing monoclonal antibody against β2AR, which could be partially antagonized by the p38-MAPK inhibitor SB203580. Moreover, shear stress stimulation, a classic non-pharmacological intervention, increased the phosphorylation levels of β2AR and enhanced the in vitro and in vivo functions of EPCs from hypertensive patients. Collectively, the current investigation demonstrated that impaired β2AR/p38MAPK/caspase-3 signaling at least partially reduced the re-endothelialization capacity of EPCs from hypertensive patients. Restoration of β2AR expression and shear stress treatment could improve their endothelial repair capacity by regulating the p38MAPK/caspase-3 signaling pathway. The clinical significance of β2AR in endothelium repair still requires further investigation.
Publication Date: 2020-12-29 00:00:00
Journal: American journal of physiology. Heart and circulatory physiology


Mediterranean diet and endothelial function in patients with coronary heart disease: An analysis of the CORDIOPREV randomized controlled trial.
Endothelial dysfunction is a crucial step in atherosclerosis development, and its severity is determinant for the risk of cardiovascular recurrence. Diet may be an effective strategy to protect the endothelium, although there is no consensus about the best dietary model. The CORonary Diet Intervention with Olive oil and cardiovascular PREVention (CORDIOPREV) study is an ongoing prospective, randomized single-blind, controlled trial in 1,002 coronary heart disease (CHD) patients, whose primary objective is to compare the effect of 2 healthy dietary patterns (low-fat versus Mediterranean diet) on the incidence of cardiovascular events. Here, we report the results of one secondary outcome of the CORDIOPREV study: to evaluate the effect of these diets on endothelial function, assessed by flow-mediated dilation (FMD) of the brachial artery. From the total participants taking part in the CORDIOPREV study, 805 completed endothelial function study at baseline and were randomized to follow a Mediterranean diet (35% fat, 22% monounsaturated fatty acids [MUFAs], and <50% carbohydrates) or a low-fat diet (28% fat, 12% MUFAs, and >55% carbohydrates), with endothelial function measurement repeated after 1 year. As secondary objectives and to explore different underlying mechanisms in the modulation of endothelial function, we quantified endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) and evaluated, in 24 preselected patients, in vitro cellular processes related to endothelial damage (reactive oxygen species, apoptosis, and senescence) and endothelial repair (cell proliferation and angiogenesis), as well as other modulators (micro-RNAs [miRNAs] and proteins). Patients who followed the Mediterranean diet had higher FMD (3.83%; 95% confidence interval [CI]: 2.91-4.23) compared with those in the low-fat diet (1.16%; 95% CI: 0.80 to 1.98) with a difference between diets of 2.63% (95% CI: 1.89-3.40, p = 0.011), even in those patients with severe endothelial dysfunction. We observed higher EPC levels (group difference: 1.64%; 95% CI: 0.79-2.13, p = 0.028) and lower EMPs (group difference: -755 EMPs/μl; 95% CI: -1,010 to -567, p = 0.015) after the Mediterranean diet compared with the low-fat diet in all patients. We also observed lower intracellular reactive oxygen species (ROS) production (group difference: 11.1; 95% CI: 2.5 to 19.6, p = 0.010), cellular apoptosis (group difference: -20.2; 95% CI: -26.7 to -5.11, p = 0.013) and senescence (18.0; 95% CI: 3.57 to 25.1, p = 0.031), and higher cellular proliferation (group difference: 11.3; 95% CI: 4.51 to 13.5, p = 0.011) and angiogenesis (total master segments length, group difference: 549; 95% CI: 110 to 670, p = 0.022) after the Mediterranean diet than the low-fat diet. Each dietary intervention was associated with distinct changes in the epigenetic and proteomic factors that modulate biological process associated with endothelial dysfunction. The evaluation of endothelial function is a substudy of the CORDIOPREV study. As in any substudy, these results should be treated with caution, such as the potential for false positives because of the exploratory nature of the analyses. Our results suggest that the Mediterranean diet better modulates endothelial function compared with a low-fat diet and is associated with a better balance of vascular homeostasis in CHD patients, even in those with severe endothelial dysfunction. URL, number NCT00924937.
Publication Date: 2020-09-10 00:00:00
Journal: PLoS medicine


A Perspective on Erythropoietin as a Potential Adjuvant Therapy for Acute Lung Injury/Acute Respiratory Distress Syndrome in Patients with COVID-19.
The novel coronavirus 2019-nCoV (SARS-CoV-2) infection that emerged in China in December 2019 has rapidly spread to become a global pandemic. This article summarizes the potential benefits of erythropoietin (EPO) in alleviating SARS-CoV-2 pathogenesis which is now called COVID-19. As with other coronavirus infection, the lethality of COVID-19 is associated with respiratory dysfunction due to overexpression of proinflammatory cytokines induced by the host immune responses. The resulting cytokine storm leads to the development of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Erythropoietin, well known for its role in the regulation of erythropoiesis, may have protective effects against ALI/ARDS induced by viral and other pathogens. EPO exerts antiapoptotic and cytoprotective properties under various pathological conditions. With a high safety profile, EPO promotes the production of endothelial progenitor cells and reduce inflammatory processes through inhibition of the nuclear factor-κB (NF-κB) and JAK-STAT3 signaling pathways. Thus, it may be considered as a safe drug candidate for COVID-19 patients if given at the early stage of the disease. The potential effects of erythropoietin on different aspects of ALI/ARDS associated with SARS-CoV-2 infection are reviewed.
Publication Date: 2020-08-31 00:00:00
Journal: Archives of medical research

smooth muscle(36)

Coadministration of endothelial and smooth muscle cells derived from human induced pluripotent stem cells as a therapy for critical limb ischemia.
Critical limb ischemia is a condition in which tissue necrosis occurs due to arterial occlusion, resulting in limb amputation in severe cases. Both endothelial cells (ECs) and vascular smooth muscle cells (SMCs) are needed for the regeneration of peripheral arteries in ischemic tissues. However, it is difficult to isolate and cultivate primary EC and SMC from patients for therapeutic angiogenesis. Induced pluripotent stem cells (iPSCs) are regarded as useful stem cells due to their pluripotent differentiation potential. In this study, we explored the therapeutic efficacy of human iPSC-derived EC and iPSC-derived SMC in peripheral artery disease model. After the induction of mesodermal differentiation of iPSC, CD34
Publication Date: 2020-11-12 00:00:00
Journal: Stem cells translational medicine

smooth muscle cells(17)

GFAP (Glial Fibrillary Acidic Protein)-Positive Progenitor Cells Contribute to the Development of Vascular Smooth Muscle Cells and Endothelial Cells-Brief Report.
While GFAP (glial fibrillary acidic protein) is commonly used as a classical marker for astrocytes in the central nervous system, GFAP-expressing progenitor cells give rise to other cell types during development. The goal of this study was to investigate whether GFAP-expressing progenitor cells contribute to the development of vascular cells in major arteries. Approach and Results: To label GFAP-expressing progenitor cells and their progeny, we crossed Our study demonstrates that vascular smooth muscle cells and endothelial cells within the same vascular segment are developmentally heterogeneous, where varying proportions of vascular smooth muscle cells and endothelial cells are contributed by GFAP-positive progenitor cells.
Publication Date: 2020-03-13 00:00:00
Journal: Arteriosclerosis, thrombosis, and vascular biology


Oligodendrocyte precursor cell specification is regulated by bidirectional neural progenitor-endothelial cell crosstalk.
Neural derived signals are crucial regulators of CNS vascularization. However, whether the vasculature responds to these signals by means of elongating and branching or in addition by building a feedback response to modulate neurodevelopmental processes remains unknown. In this study, we identified bidirectional crosstalk between the neural and the vascular compartment of the developing CNS required for oligodendrocyte precursor cell specification. Mechanistically, we show that neural progenitor cells (NPCs) express angiopoietin-1 (Ang1) and that this expression is regulated by Sonic hedgehog. We demonstrate that NPC-derived Ang1 signals to its receptor, Tie2, on endothelial cells to induce the production of transforming growth factor beta 1 (TGFβ1). Endothelial-derived TGFβ1, in turn, acts as an angiocrine molecule and signals back to NPCs to induce their commitment toward oligodendrocyte precursor cells. This work demonstrates a true bidirectional collaboration between NPCs and the vasculature as a critical regulator of oligodendrogenesis.
Publication Date: 2021-01-30 00:00:00
Journal: Nature neuroscience

endothelial progenitor cell transplantation(17)

Endothelial progenitor cell transplantation restores vascular injury in mice after whole-brain irradiation.
Vascular damage plays an important role in the pathogenesis of radiation-induced brain injury (RBI). Endothelial progenitor cells (EPCs) are responsible for maintaining and repairing endothelial function, and have become a promising method for the treatment of cerebrovascular diseases. However, whether EPC transplantation plays a protective role in RBI has not been fully elucidated. Therefore, the present study investigated the effects of bone marrow-derived EPC transplantation in a whole-brain irradiation (WBI) mouse model. Mice were divided into the three groups: control group, irradiation group and EPCs group. Phosphate buffered saline or EPCs were intravenously injected into mice one week after irradiation, and brains were analyzed eight weeks after injection. Flow cytometry demonstrated that irradiation led to a significant reduction in the peripheral blood EPC count; however, EPC transplantation led to a significant increase in the circulating EPCs. Intravital two-photon imaging and western blotting demonstrated that EPC transplantation reversed the effects of irradiation by decreasing blood-brain barrier permeability and increasing the expression of tight junction proteins in the brain. Additionally, immunofluorescence staining revealed that the brain microvascular density was higher in the EPCs group than the irradiation group. Therefore, EPC transplantation may restore damage caused by WBI to the blood-brain barrier, tight junctions, and cerebral capillary density. These results highlight the potential beneficial effects of EPC transplantation on vascular damage induced by RBI.
Publication Date: 2020-07-06 00:00:00
Journal: Brain research


Neural Progenitor Cell-Derived Extracellular Vesicles Enhance Blood-Brain Barrier Integrity by NF-κB (Nuclear Factor-κB) Dependent Regulation of ABCB1 (ATP-Binding Cassette Transporter B1) in Stroke Mice.
Extracellular vesicles (EVs) derived from neural progenitor cells enhance poststroke neurological recovery, albeit the underlying mechanisms remain elusive. Since previous research described an enhanced poststroke integrity of the blood-brain barrier (BBB) upon systemic transplantation of neural progenitor cells, we examined if neural progenitor cell-derived EVs affect BBB integrity and which cellular mechanisms are involved in the process. Approach and Results: Using in vitro models of primary brain endothelial cell (EC) cultures as well as co-cultures of brain ECs (ECs) and astrocytes exposed to oxygen glucose deprivation, we examined the effects of EVs or vehicle on microvascular integrity. In vitro data were confirmed using a mouse transient middle cerebral artery occlusion model. Cultured ECs displayed increased ABCB1 (ATP-binding cassette transporter B1) levels when exposed to oxygen glucose deprivation, which was reversed by treatment with EVs. The latter was due to an EV-induced inhibition of the NF-κB (nuclear factor-κB) pathway. Using a BBB co-culture model of ECs and astrocytes exposed to oxygen glucose deprivation, EVs stabilized the BBB and ABCB1 levels without affecting the transcellular electrical resistance of ECs. Likewise, EVs yielded reduced Evans blue extravasation, decreased ABCB1 expression as well as an inhibition of the NF-κB pathway, and downstream matrix metalloproteinase 9 (MMP-9) activity in stroke mice. The EV-induced inhibition of the NF-κB pathway resulted in a poststroke modulation of immune responses. Our findings suggest that EVs enhance poststroke BBB integrity via ABCB1 and MMP-9 regulation, attenuating inflammatory cell recruitment by inhibition of the NF-κB pathway.
Publication Date: 2020-12-18 00:00:00
Journal: Arteriosclerosis, thrombosis, and vascular biology

systemic lupus erythematosus(12)

IFN-I Mediates Dysfunction of Endothelial Progenitor Cells in Atherosclerosis of Systemic Lupus Erythematosus.
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease including the cardiovascular system. Atherosclerosis is the most common cardiovascular complication of SLE and a significant risk factor for morbidity and mortality. Vascular damage/protection mechanism in SLE patients is out of balance, caused by the cascade reaction among oxidative stress, proinflammatory cytokines, Neutrophil Extracellular Traps, activation of B cells and autoantibodies and abnormal T cells. As a precursor cell repairing vascular endothelium, endothelial progenitor cells (EPCs) belong to the protective mechanism and show the reduced number and impaired function in SLE. However, the pathological mechanism of EPCs dysfunction in SLE remains ill-defined. This paper reviews the latest SLE epidemiology and pathogenesis, discusses the changes in the number and function of EPCs in SLE, expounds the role of EPCs in SLE atherosclerosis, and provides new guidance and theoretical basis for exploring novel targets for SLE treatment.
Publication Date: 2020-12-03 00:00:00
Journal: Frontiers in immunology


1-Year COMBO stent outcomes stratified by the PARIS bleeding prediction score: From the MASCOT registry.
The COMBO stent is a biodegradable-polymer sirolimus-eluting stent with endothelial progenitor cell capture technology for faster endothelialization. We analyzed COMBO stent outcomes in relation to bleeding risk using the PARIS bleeding score. MASCOT was an international registry of all-comers undergoing attempted COMBO stent implantation. We stratified patients as low bleeding-risk (LBR) for PARIS score ≤ 3 and intermediate-to-high (IHBR) for score > 3 based on baseline age, body mass index, anemia, current smoking, chronic kidney disease and need for triple therapy. Primary endpoint was 1-year target lesion failure (TLF), composite of cardiac death, myocardial infarction (MI) not clearly attributed to a non-target vessel or clinically-driven target lesion revascularization (TLR). Bleeding was adjudicated using the Bleeding Academic Research Consortium (BARC) definition. Dual antiplatelet therapy (DAPT) cessation was independently adjudicated. The study included 56% (n = 1270) LBR and 44% (n = 1009) IHBR patients. Incidence of 1-year TLF was higher in IHBR patients (4.1% vs. 2.6%, p = 0.047) driven by cardiac death (1.7% vs. 0.7%, p = 0.029) with similar rates of MI (1.8% vs. 1.1%, p = 0.17), TLR (1.5% vs. 1.6%, p = 0.89) and definite/ probable stent thrombosis (1.2% vs. 0.6%, p = 0.16). Incidence of 1-year major BARC 3 or 5 bleeding was significantly higher in IHBR patients (2.3% vs. 0.9%, p = 0.0094), as was the incidence of DAPT cessation (29.3% vs. 22.8%, p < 0.01), driven by physician-guided discontinuation. Patients with intermediate-to-high PARIS bleeding risk in the MASCOT registry experienced greater incidence of 1-year TLF, major bleeding and DAPT cessation than LBR patients, without significant differences in stent thrombosis.
Publication Date: 2020-09-22 00:00:00
Journal: International journal of cardiology. Heart & vasculature

diabetic patients(20)

Effect of negative-pressure wound therapy on the circulating number of peripheral endothelial progenitor cells in diabetic patients with mild to moderate degrees of ischaemic foot ulcer.
Publication Date: 2019-03-08 00:00:00
Journal: Vascular