Prospective Isolation of ISL1 Cardiac Progenitors from Human ESCs for Myocardial Infarction Therapy.

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 identified ALCAM (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.