Endothelial cells serve as a cardiac progenitor population in the adult heart during homeostasis and contribute to repair after ischemic injury

Abstract

Cardiac tissue undergoes renewal with low rates. Although resident stem cell populations have been identified to support cardiomyocyte turnover, the source of the cardiac stem cells and their niche remain elusive. Using Cre/Lox-based cell lineage tracing strategies, we discovered that labeling of endothelial cells (ECs) in the adult heart yields progeny with cardiac stem cell characteristics that express Gata4 and Sca1. Endothelial-derived cardiac progenitor cells were localized in the arterial coronary walls with quiescent and proliferative cells in the media and adventitia layers, respectively. Within myocardium, we identified labeled cardiomyocytes organized in clusters of single-cell origin. Pulse-chase experiments showed that generation of individual clusters was rapid, but confined to specific regions of the heart, primarily in the right anterior and left posterior ventricular walls and the junctions between the two ventricles. By contrast, the regenerative rates of endothelial-like progenitors declined after acute (myocardial infarction) or chronic (angiotensin II-induced hypertension) injury. These cells alternatively contributed almost exclusively to scar tissue formation through generation of infarct myofibroblasts. Our findings suggest an EC-like progenitor population with cardiomyogenic regenerative capacity exists in the adult heart, and replenishes high turnover CMs within localized ventricular sites. However, after cardiac injury, these progenitor cells acquire a pro-fibrotic phenotype. Understanding the biology of this novel adult progenitor population may lead to new methods of enhancing the regenerative capacity of the heart after acute ischemic injury or during heart failure.