title: Suppression of Transforming Growth Factor-β Signaling Delays Cellular Senescence and Preserves the Function of Endothelial Cells Derived from Human Pluripotent Stem Cells.
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-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, 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. Stem Cells Translational Medicine 2017;6:589-600.
authors.affiliation: Division of Hematology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Bai
authors.affiliation: Division of Hematology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Yongxing
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Division of Hematology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Dixie L
authors.initials: DL
authors.lastname: Hoyle
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences, Tianjin, People's Republic of China.|Tianjin Key Laboratory of Blood Cell Therapy and Technology, Tianjin, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Division of Hematology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences, Tianjin, People's Republic of China.|Tianjin Key Laboratory of Blood Cell Therapy and Technology, Tianjin, People's Republic of China.
authors.forename: Zack Z
authors.initials: ZZ
authors.lastname: Wang
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D016922:Cellular Senescence / Q000187:drug effects*; D016895:Culture Media, Serum-Free / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology*; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells / Q000187:drug effects* / Q000378:metabolism / Q000637:transplantation; D000066449:Human Embryonic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000637:transplantation; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D008077:Lipoproteins, LDL / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D000077293:Receptor, Transforming Growth Factor-beta Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; C493956:CDKN1A protein, human; C000614131:CDKN2A protein, human; C493966:CDKN2B protein, human; D016895:Culture Media, Serum-Free; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004149:Dioxoles; D008077:Lipoproteins, LDL; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C032629:acetyl-LDL; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human
keywords: Endothelial cells; Human pluripotent stem cells; Senescence; Transforming growth factor-β