TY - JOUR
T1 - Suppression of transforming growth factor-β signaling delays cellular senescence and preserves the function of endothelial cells derived from human pluripotent stem cells
AU - Bai, Hao
AU - Gao, Yongxing
AU - Hoyle, Dixie L.
AU - Cheng, Tao
AU - Wang, Zack Z.
N1 - Funding Information:
This work was partially supported by Maryland State Stem Cell Research Fund Grant 2012-MSCRFII-0124 and NIH/National Institute of Diabetes and Digestive and Kidney Diseases Grant R01 DK106109. Additional technical supportwas provided by the Ross Flow Cytometry Core Facility at Johns Hopkins School of Medicine.
Publisher Copyright:
© AlphaMed Press, 2016 The Authors.
PY - 2017/2
Y1 - 2017/2
N2 - Transplantation of vascular cells derived from human pluripotent stem cells (hPSCs) offers an attractive noninvasive method for repairing the ischemic tissues and for preventing the progression of vascular diseases. Here, we found that in a serum-free condition, the proliferation rate of hPSC-derived endothelial cells is quickly decreased, accompanied with an increased cellular senescence, resulting in impaired gene expression of endothelial nitric oxide synthase (eNOS) and impaired vessel forming capability in vitro and in vivo. To overcome the limited expansion of hPSC-derived endothelial cells, wescreened small molecules for specific signaling pathways and found that inhibition of transforming growth factor-β (TGF-β) signaling significantly retarded cellular senescence and increased a proliferative index of hPSC-derived endothelial cells. Inhibition of TGF-β signaling extended the life span of hPSC-derived endothelial and improved endothelial functions, including vascular network formation on Matrigel, acetylated low-density lipoprotein uptake, and eNOS expression. Exogenous transforming growth factor-β 1 increased the gene expression of cyclin-dependent kinase inhibitors, p15Ink4b, p16Ink4a, and p21CIP1, in endothelial cells. Conversely, inhibition of TGF-β reduced the gene expression of p15Ink4b, p16Ink4a, and p21CIP1. Our findings demonstrate that the senescence of newly generated endothelial cells from hPSCs is mediated by TGF-β signaling, and manipulation of TGF-β signaling offers a potential target to prevent vascular aging.
AB - Transplantation of vascular cells derived from human pluripotent stem cells (hPSCs) offers an attractive noninvasive method for repairing the ischemic tissues and for preventing the progression of vascular diseases. Here, we found that in a serum-free condition, the proliferation rate of hPSC-derived endothelial cells is quickly decreased, accompanied with an increased cellular senescence, resulting in impaired gene expression of endothelial nitric oxide synthase (eNOS) and impaired vessel forming capability in vitro and in vivo. To overcome the limited expansion of hPSC-derived endothelial cells, wescreened small molecules for specific signaling pathways and found that inhibition of transforming growth factor-β (TGF-β) signaling significantly retarded cellular senescence and increased a proliferative index of hPSC-derived endothelial cells. Inhibition of TGF-β signaling extended the life span of hPSC-derived endothelial and improved endothelial functions, including vascular network formation on Matrigel, acetylated low-density lipoprotein uptake, and eNOS expression. Exogenous transforming growth factor-β 1 increased the gene expression of cyclin-dependent kinase inhibitors, p15Ink4b, p16Ink4a, and p21CIP1, in endothelial cells. Conversely, inhibition of TGF-β reduced the gene expression of p15Ink4b, p16Ink4a, and p21CIP1. Our findings demonstrate that the senescence of newly generated endothelial cells from hPSCs is mediated by TGF-β signaling, and manipulation of TGF-β signaling offers a potential target to prevent vascular aging.
KW - Endothelial cells
KW - Human pluripotent stem cells
KW - Senescence
KW - Transforming growth factor-β
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UR - http://www.scopus.com/inward/citedby.url?scp=85017572339&partnerID=8YFLogxK
U2 - 10.5966/sctm.2016-0089
DO - 10.5966/sctm.2016-0089
M3 - Article
C2 - 28191769
AN - SCOPUS:85017572339
SN - 2157-6564
VL - 6
SP - 589
EP - 600
JO - Stem Cells Translational Medicine
JF - Stem Cells Translational Medicine
IS - 2
ER -