Specific mesoderm subset derived from human pluripotent stem cells ameliorates microvascular pathology in type 2 diabetic mice.

Abstract

Human induced pluripotent stem cells (hiPSCs) were differentiated into a specific mesoderm subset characterized by KDR⁺CD56⁺APLNR⁺ (KNA⁺) expression. KNA⁺ cells had high clonal proliferative potential and specification into endothelial colony-forming cell (ECFCs) phenotype. KNA⁺ cells differentiated into perfused blood vessels when implanted subcutaneously into the flank of nonobese diabetic/severe combined immunodeficient mice and when injected into the vitreous of type 2 diabetic mice (<i>db/db</i> mice). Transcriptomic analysis showed that differentiation of hiPSCs derived from diabetics into KNA⁺ cells was sufficient to change baseline differences in gene expression caused by the diabetic status and reprogram diabetic cells to a pattern similar to KNA⁺ cells derived from nondiabetic hiPSCs. Proteomic array studies performed on retinas of <i>db/db</i> mice injected with either control or diabetic donor-derived KNA⁺ cells showed correction of aberrant signaling in <i>db/db</i> retinas toward normal healthy retina. These data provide "proof of principle" that KNA⁺ cells restore perfusion and correct vascular dysfunction in <i>db/db</i> mice.