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

Chang Hyun Gil, Dibyendu Chakraborty, Cristiano P. Vieira, Nutan Prasain, Sergio Li Calzi, Seth D. Fortmann, Ping Hu, Kimihiko Banno, Mohamed Jamal, Chao Huang, Micheli S. Sielski, Yang Lin, Xinxin Huang, Mariana D. Dupont, Jason L. Floyd, Ram Prasad, Ana Leda F. Longhini, Trevor J. McGill, Hyung Min Chung, Michael P. MurphyDarrell N. Kotton, Michael E. Boulton, Mervin C. Yoder, Maria B. Grant

Research output: Contribution to journalArticlepeer-review

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 (db/db 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 db/db mice injected with either control or diabetic donor- derived KNA+ cells showed correction of aberrant signaling in db/db retinas toward normal healthy retina. These data provide "proof of principle"that KNA+ cells restore perfusion and correct vascular dysfunction in db/db mice.

Original languageEnglish (US)
Article numbereabm5559
JournalScience Advances
Volume8
Issue number9
DOIs
StatePublished - Mar 2022

ASJC Scopus subject areas

  • General

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