4-(5-benzo(1-3)dioxol-5-yl-4-pyridin-2-yl-1h-imidazol-2-yl)benzamide and Ischemia

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

Topics: Animals; Benzamides; Cell Line; Cell Proliferation; Cellular Senescence; Culture Media, Serum-Free; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21; Dioxoles; Disease Models, Animal; Endothelial Progenitor Cells; Human Embryonic Stem Cells; Humans; Ischemia; Lipoproteins, LDL; Mice, Inbred NOD; Mice, SCID; Neovascularization, Physiologic; Nitric Oxide Synthase Type III; Phenotype; Receptor, Transforming Growth Factor-beta Type I; Signal Transduction; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1