Closing the Mitochondrial Permeability Transition Pore in hiPSC-Derived Endothelial Cells Induces Glycocalyx Formation and Functional Maturation

摘要

Human induced pluripotent stem cells (hiPSCs) are used to study organogenesis and model disease as well as being developed for regenerativemedicine. Endothelial cells are among the many cell types differentiated from hiPSCs, but their maturation and stabilization fallshort of that in adult endothelium. We examined whether shear stress alone or in combination with pericyte co-culture would induceflow alignment and maturation of hiPSC-derived endothelial cells (hiPSC-ECs) but found no effects comparable with those in primarymicrovascular ECs. In addition, hiPSC-ECs lacked a luminal glycocalyx, critical for vasculature homeostasis, shear stress sensing, andsignaling. We noted, however, that hiPSC-ECs have dysfunctional mitochondrial permeability transition pores, resulting in reducedmitochondrial function and increased reactive oxygen species. Closure of these pores by cyclosporine A improved EC mitochondrialfunction but also restored the glycocalyx such that alignment to flow took place. These results indicated that mitochondrial maturationis required for proper hiPSC-EC functionality.