Multipotent Vasculogenic Pericytes From Human Pluripotent Stem Cells Promote Recovery of Murine Ischemic Limb

TLDR

Pericytes are perivascular cells with angiogenic functions and mesenchymal stem cell–like properties, yet their emergence during human pluripotent stem cell (hPSC) maturation has not been described. The study aimed to derive and isolate multipotent CD105⁺CD90⁺CD73⁺CD31⁻ mesodermal precursors from hPSC embryoid bodies that can be expanded and differentiated into pericytes. The resulting pericytes expressed CD146, NG2, and PDGFRβ, rapidly anastomosed with co‑implanted endothelial cells, and when transplanted into ischemic mouse limbs, promoted vascular and muscle regeneration, with donor cells integrating into regenerated tissue by day 21.

Abstract

Pericytes represent a unique subtype of microvessel-residing perivascular cells with diverse angiogenic functions and multilineage developmental features of mesenchymal stem cells. Although various protocols for derivation of endothelial and/or smooth muscle cells from human pluripotent stem cells (hPSC, either embryonic or induced) have been described, the emergence of pericytes in the course of hPSC maturation has not yet been elucidated.We found that during hPSC development, spontaneously differentiating embryoid bodies give rise to CD105(+)CD90(+)CD73(+)CD31(-) multipotent clonogenic mesodermal precursors, which can be isolated and efficiently expanded. Isolated and propagated cells expressed characteristic pericytic markers, including CD146, NG2, and platelet-derived growth factor receptor β, but not the smooth muscle cell marker α-smooth muscle actin. Coimplantation of hPSC-derived endothelial cells with pericytes resulted in functional and rapid anastomosis to the murine vasculature. Administration of pericytes into immunodeficient mice with limb ischemia promoted significant vascular and muscle regeneration. At day 21 after transplantation, recruited hPSC pericytes were found incorporated into recovered muscle and vasculature.Derivation of vasculogenic and multipotent pericytes from hPSC can be used for the development of vasculogenic models using multiple vasculogenic cell types for basic research and drug screening and can contribute to angiogenic regenerative medicine.