Human Telomerase M-RNA Rescues Cellular Functions, Gene Regulation, and Chromatin Structure in Progeria Ipsc-Derived Endothelial Cells

Hutchinson-Gilford progeria syndrome (HGPS) is a progressive aging syndrome caused by a single mutation (C1824T) in the Lamin A/C gene (LMNA). These patients succumb in their teen years to accelerated coronary and carotid artery disease. To understand the mechanisms of accelerated vascular aging, we used induced pluripotent stem cells (iPSCs) derived from skin fibroblasts of the children (HGPS), or from their unaffected parents (CTL). We differentiated the iPSCs into endothelial (ECs). By comparison to CTL, the HGPS ECs had markedly impaired cell proliferation, synthesis of nitric oxide, ac-LDL uptake, matrigel network formation in vitro and generation of capillaries in matrigel plugs in vivo. Further, we noted cellular hallmarks of aging, including increased generation of inflammatory cytokines, shorter telomeres, and greater frequency of nuclear dysmorphia. Treatment of ECs with human telomerase …