Suppression of Transforming Growth Factor-ß Signaling Delays Cellular Senescence and Preserves the Function of Endothelial Cells Derived from Human Pluripotent Stem Cells.
Stem Cells Transl Med
; 6(2): 589-600, 2017 02.
Article
em En
| MEDLINE
| ID: mdl-28191769
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, we screened small molecules for specific signaling pathways and found that inhibition of transforming growth factor-ß (TGF-ß) signaling significantly retarded cellular senescence and increased a proliferative index of hPSC-derived endothelial cells. Inhibition of TGF-ß 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-ß1 increased the gene expression of cyclin-dependent kinase inhibitors, p15Ink4b , p16Ink4a , and p21CIP1 , in endothelial cells. Conversely, inhibition of TGF-ß 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-ß signaling, and manipulation of TGF-ß signaling offers a potential target to prevent vascular aging. Stem Cells Translational Medicine 2017;6589-600.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Benzamidas
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Fator de Crescimento Transformador beta
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Senescência Celular
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Proliferação de Células
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Dioxóis
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Células Progenitoras Endoteliais
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Células-Tronco Embrionárias Humanas
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Receptor do Fator de Crescimento Transformador beta Tipo I
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Stem Cells Transl Med
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos