期刊
STEM CELLS TRANSLATIONAL MEDICINE
卷 6, 期 2, 页码 589-600出版社
OXFORD UNIV PRESS
DOI: 10.5966/sctm.2016-0089
关键词
Endothelial cells; Human pluripotent stem cells; Senescence; Transforming growth factor-beta
资金
- Maryland State Stem Cell Research Fund Grant [2012-MSCRFII-0124]
- NIH/National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK106109]
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, we screened small molecules for specific signaling pathways and found that inhibition of transforming growth factor-beta (TGF-beta) signaling significantly retarded cellular senescence and increased a proliferative index of hPSC-derived endothelial cells. Inhibition of TGF-beta 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-beta 1 increased the gene expression of cyclin-dependent kinase inhibitors, p15(Ink4b), p16(Ink4a), and p21(CIP1), in endothelial cells. Conversely, inhibition of TGF-beta reduced the gene expression of p15(Ink4b), p16(Ink4a), and p21(CIP1). Our findings demonstrate that the senescence of newly generated endothelial cells from hPSCs is mediated by TGF-beta signaling, and manipulation of TGF-beta signaling offers a potential target to prevent vascular aging.
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