Endothelial progenitor cells give rise to pro-angiogenic smooth muscle-like progeny (original) (raw)
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Transdifferentiation of human endothelial progenitors into smooth muscle cells
Biomaterials, 2016
Access to smooth muscle cells (SMC) would create opportunities for tissue engineering, drug testing, and disease modeling. Herein we report the direct conversion of human endothelial progenitor cells (EPC) to induced smooth muscle cells (iSMC) by induced expression of MYOCD. The EPC undergo a cytoskeletal rearrangement resembling that of mesenchymal cells within 3 days post initiation of MYOCD expression. By day 7, the reprogrammed cells show upregulation of smooth muscle markers ACTA2, MYH11, and TAGLN by qRT-PCR and ACTA2 and MYH11 expression by immunofluorescence. By two weeks, they resemble umbilical artery SMC in microarray gene expression analysis. The iSMC, in contrast to EPC control, show calcium transients in response to phenylephrine stimulation and a contractility an order of magnitude higher than that of EPC as determined by traction force microscopy. Tissue-engineered blood vessels constructed using iSMC show functionality with respect to flowand drug-mediated vasodilation and vasoconstriction.
The Anatomical Record, 2003
Vascular smooth muscle cells (SMCs) originate from multiple types of progenitor cells. In the embryo, the most well studied SMC progenitor is the cardiac neural crest stem cell. Smooth muscle differentiation in the neural crest lineage is controlled by a combination of cell intrinsic factors, including Pax3, Tbx1, FoxC1, and serum response factor, interacting with various extrinsic factors in the local environment such as bone morphogenetic proteins (BMPs), Wnts, endothelin (ET)-1, and FGF8. Additional sources of multipotential cells that give rise to vascular SMCs in the embryo include proepicardial cells and possibly endothelial progenitor cells. In the adult, vascular SMCs must continually repair arterial injuries and maintain functional mass in response to changing demands upon the vessel wall. Recent evidence suggests that this is accomplished, in part, by recruiting multipotential vascular progenitors from bone marrow-derived stem cells as well as from less well defined sources within adult tissues themselves. This article will review our current understanding of the origins of vascular SMCs from multipotential stem and progenitor cells in developing as well as adult vasculature. Anat Rec Part A 276A: 22-33, 2004.
Cardiovascular Research, 2010
Time for primary review: 29 days Aims Endothelial progenitor cells (EPC) have been shown to repair pulmonary endothelium, although they can also migrate into the arterial intima and differentiate into smooth muscle-like (mesenchymal) cells contributing to intimal hyperplasia. The molecular mechanisms by which this process proceeds have not been fully elucidated. Here, we study whether genes involved in the endothelial-to-mesenchymal transition (EnMT) may contribute to the mesenchymal phenotype acquisition of EPC and we evaluate whether transforming growth factor b1 (TGFb1) is involved in this process. Methods and results Our results show that co-culture of EPC with smooth muscle cells (SMC) increases the expression of the mesenchymal cell markers a-smooth muscle actin, sm22-a, and myocardin, and decreases the expression of the endothelial cell marker CD31. In the same conditions, we also observed a concomitant increase in the gene expression of the EnMT-related transcription factors: slug, snail, zeb1, and endothelin-1. This indicates that mesenchymal phenotype acquisition occurred through an EnMT-like process. Inhibition of TGFb receptor I (TGFbRI) downregulated snail gene expression, blocked the EnMT, and facilitated the differentiation of EPC to the endothelial cell lineage. Furthermore, TGFbRI inhibition decreased migration of EPC stimulated by SMC without affecting their functionality and adhesion capacity. Conclusion These results indicate that EPC may differentiate into SMC-like cells through an EnMT-like process and that TGFbI plays an important role in the fate of EPC.
Concurrent generation of functional smooth muscle and endothelial cells via a vascular progenitor
Stem cells translational medicine, 2014
Smooth muscle cells (SMCs) and endothelial cells (ECs) are typically derived separately, with low efficiencies, from human pluripotent stem cells (hPSCs). The concurrent generation of these cell types might lead to potential applications in regenerative medicine to model, elucidate, and eventually treat vascular diseases. Here we report a robust two-step protocol that can be used to simultaneously generate large numbers of functional SMCs and ECs from a common proliferative vascular progenitor population via a two-dimensional culture system. We show here that coculturing hPSCs with OP9 cells in media supplemented with vascular endothelial growth factor, basic fibroblast growth factor, and bone morphogenetic protein 4 yields a higher percentage of CD31(+)CD34(+) cells on day 8 of differentiation. Upon exposure to endothelial differentiation media and SM differentiation media, these vascular progenitors were able to differentiate and mature into functional endothelial cells and smooth...
Smooth Muscle Progenitor Cells in Human Blood
Circulation, 2002
Background-Recent animal data suggest that vascular smooth muscle cells within the neointima of the vessel wall may originate from bone marrow, providing indirect evidence for circulating smooth muscle progenitor cells (SPCs). Evidence for circulating SPCs in human subjects does not exist, and the mechanism whereby such putative SPCs may home to sites of plaque formation is presently not understood but is likely to involve expression of specific surface adhesion molecules, such as integrins. In this study, we aimed to culture smooth muscle outgrowth cells (SOCs) from SPCs in human peripheral blood and characterize surface integrin expression on these cells. Methods and Results-Human mononuclear cells isolated from buffy coat were seeded on collagen type 1 matrix and outgrowth cells selected in endothelial growth medium (EGM-2) or EGM-2 and platelet-derived growth factor BB. Selection in platelet-derived growth factor BB-enriched medium caused rapid outgrowth and expansion of SOC to Ͼ40 population doublings in a 4-month period. These SOCs were positive for smooth muscle cell-specific ␣ actin (␣SMA), myosin heavy chain, and calponin on immunofluorescence and Western blotting and were also positive for CD34, Flt1, and Flk1 receptor but negative for Tie-2 receptor expression, suggesting a potential bone marrow angioblastic origin. In contrast, endothelial outgrowth cells (EOCs) grown in EGM-2 alone and the initial MNC population were negative for these smooth muscle-specific markers. Integrin ␣ 5  1 expression by FACS and Western blotting was significantly increased in SOCs compared with EOCs, and this was confirmed by 8-fold greater adhesion of SOC to fibronectin (PϽ0.001), an effect that could be decreased using an ␣ 5  1 antibody. Finally, SOC showed a significantly greater in vitro proliferative potential compared with EOCs of similar passage (PϽ0.001). Conclusions-This study demonstrates for the first time outgrowth of smooth muscle cells with a specific growth, adhesion, and integrin profile from putative SPC in human blood. These data have implications for our understanding of adult vascular smooth muscle cell differentiation, proliferation, and homing.
Circulation Research, 2008
Cell-based therapy is a promising approach designed to enhance neovascularization and function of ischemic tissues. Interaction between endothelial and smooth muscle cells regulates vessels development and remodeling and is required for the formation of a mature and functional vascular network. Therefore, we assessed whether coadministration of endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs) can increase the efficiency of cell therapy. Unilateral hindlimb ischemia was surgically induced in athymic nude mice treated with or without intravenous injection of EPCs (0.5ϫ10 6 ), SMPCs (0.5ϫ10 6 ) and EPCsϩSMPCs (0.25ϫ10 6 ϩ0.25ϫ10 6 ). Vessel density and foot perfusion were increased in mice treated with EPCsϩSMPCs compared to animals receiving EPCs alone or SMPCs alone (PϽ0.001). In addition, capillary and arteriolar densities were enhanced in EPCϩSMPC-treated mice compared to SMPC and EPC groups (PϽ0.01). We next examined the role of Ang-1/Tie2 signaling in the beneficial effect of EPC and SMPC coadministration. Small interfering RNA directed against Ang-1-producing SMPCs or Tie2-expressing EPCs blocked vascular network formation in Matrigel coculture assays, reduced the rate of incorporated EPCs within vascular structure, and abrogated the efficiency of cell therapy. Production of Ang-1 by SMPCs activates Tie2-expressing EPCs, resulting in increase of EPC survival and formation of a stable vascular network. Subsequently, the efficiency of EPC-and SMPC-based cotherapy is markedly increased. Therefore, coadministration of different types of vascular progenitor cells may constitute a novel therapeutic strategy for improving the treatment of ischemic diseases. (Circ Res. 2008;103:751-760.)
Generation and Characterization of Human Mesenchymal Stem Cell-Derived Smooth Muscle Cells
International Journal of Molecular Sciences
Cardiovascular diseases are the leading cause of death worldwide. A completely autologous treatment can be achieved by using elastogenic mesenchymal stem cell (MSC)-derived smooth muscle cells (SMC) at the affected tissue site of vascular diseases such as abdominal aortic aneurysms (AAA). Thus, our work focused on evaluating the efficacy of (a) the combination of various growth factors, (b) different time periods and (c) different MSC lines to determine the treatment combination that generated SMCs that exhibited the greatest elastogenicity among the tested groups using Western blotting and flow cytometry. Additionally, total RNA sequencing was used to confirm that post-differentiation cells were upregulating SMC-specific gene markers. Results indicated that MSCs cultured for four days in PDGF + TGFβ1 (PT)-infused differentiation medium showed significant increases in SMC markers and decreases in MSC markers compared to MSCs cultured without differentiation factors. RNA Seq analysis...
Biomolecular Engineering, 2007
Appropriate matrix formation, turnover and remodeling in tissue-engineered small diameter vascular conduits are crucial for their long-term function. The interaction between cells and extra-cellular components is indispensable in determining cellular behavior in tissues and on biomaterials. The fibrin that contains fibronectin shows promise in most aspects as a tissue engineering scaffold, whereas, deposition of elastin and collagen by endothelial cells grown in the lumen of the construct is desirable to improve post implant retention, mechanical stability and vasoresponsiveness. So far there is no report on production of extra-cellular matrix (ECM) proteins, elastin and collagen by endothelial cells (EC) in in vitro culture conditions. In this study, we have used a biomimetic approach of providing multiple growth factors (GF) in the fibronectin (FN)containing fibrin matrix to induce production of elastin and collagen by the endothelial cells for application in vascular tissue engineering. Deposition of elastin and collagens with matrix remodeling is demonstrated through qualitative analysis of the matrices that were recovered after growing cells on the initial fibrin-FN-GF matrix. Expressions of mRNA for both proteins were assessed by real time polymerase chain reaction (RT-PCR) to estimate the effects of multiple growth factor compositions. Marked deposition of elastin and collagen was evidenced by staining the recovered matrix after different culture intervals. Obviously, the biomimetic environment created by adding angiogenic and platelet growth factors in the fibrin-fibronectin-gelatin matrix can induce deposition of collagens and elastin by EC.