Prospective Isolation of ISL1(+) Cardiac Progenitors from Human ESCs for Myocardial Infarction Therapy

Abstract

The LIM-homeodomain transcription factor ISL1 marks multipotent cardiac progenitors that give rise to cardiac muscle, endothelium, and smooth muscle cells. ISL1(+) progenitors can be derived from human pluripotent stem cells, but the inability to efficiently isolate pure populations has limited their characterization. Using a genetic selection strategy, we were able to highly enrich ISL1(+) cells derived from human embryonic stem cells. Comparative quantitative proteomic analysis of enriched ISL1(+) cells identifiedALCAM( CD166) as a surface marker that enabled the isolation of ISL1(+) progenitor cells. ALCAM(+)/ISL1(+) progenitors are multipotent and differentiate into cardiomyocytes, endothelial cells, and smooth muscle cells. Transplantation of ALCAM(+) progenitors enhances tissue recovery, restores cardiac function, and improves angiogenesis through activation of AKT-MAPK signaling in a rat model of myocardial infarction, based on cardiac MRI and histology. Our study establishes an efficient method for scalable purification of human ISL1(+) cardiac precursor cells for therapeutic applications.