Open AccessSuppression of Transforming Growth Factor‐β Signaling Delays Cellular Senescence and Preserves the Function of Endothelial Cells Derived from Human Pluripotent Stem Cells
Author(s) -
Bai Hao,
Gao Yongxing,
Hoyle Dixie L.,
Cheng Tao,
Wang Zack Z.
Publication year - 2017
Publication title -
stem cells translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.781
H-Index - 71
eISSN - 2157-6580
pISSN - 2157-6564
DOI - 10.5966/sctm.2016-0089
Subject(s) - microbiology and biotechnology , induced pluripotent stem cell , biology , senescence , endothelial stem cell , matrigel , stem cell , transforming growth factor , vascular endothelial growth factor , signal transduction , vascular endothelial growth factor b , cancer research , vascular endothelial growth factor a , embryonic stem cell , angiogenesis , in vitro , biochemistry , gene , vegf receptors
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‐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‐β1 increased the gene expression of cyclin‐dependent kinase inhibitors, p15 Ink4b , p16 Ink4a , and p21 CIP1 , in endothelial cells. Conversely, inhibition of TGF‐β 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‐β signaling, and manipulation of TGF‐β signaling offers a potential target to prevent vascular aging. S tem C ells T ranslational M edicine 2017;6:589–600