Suppression of transforming growth factor-β signaling delays cellular senescence and preserves the function of endothelial cells derived from human pluripotent stem cells

Hao Bai, Yongxing Gao, Dixie L. Hoyle, Tao Cheng, Zack Z. Wang

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)589-600
Number of pages12
JournalStem cells translational medicine
Volume6
Issue number2
DOIs
Publication statusPublished - Feb 1 2017

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Keywords

  • Endothelial cells
  • Human pluripotent stem cells
  • Senescence
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

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