Endothelial Cells Contribute to Generation of Adult Ventricular Myocytes during Cardiac Homeostasis

Abstract

SUMMARY 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 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. Our data demonstrate that endothelial cells are an intrinsic component of the cardiac renewal process.

cKit + cardiac progenitors of neural crest origin

“…Furthermore, the findings are in agreement with previous reports supporting the existence of cKit + CPs, which do not contribute to coronary endothelium (15), as well as with recent endothelial lineage fate-mapping analyses suggesting that the coronary endothelium is unlikely to originate from cKit + cells (6,29).…”

“…Our study differs from a recent cardiac genetic fate-map of cKit, using different cKit alleles (21). First, in contrast to findings presented here and elsewhere (6,15,29), van Berlo et al (21) reported that cKit CPs contribute extensively to coronary endothelium. However, it is noteworthy that mutations in the mouse W/cKit locus have not been associated with tangible cardiovascular defects (12), as would be likely if cKit + CPs comprised a major source of coronary vascular cells.…”

“…For example, the myocardial lineage originally develops from cardiac progenitors (CPs) of mesodermal origin (2)(3)(4)(5), which form the first and second heart fields. However, later during morphogenesis, the cardiomyogenic program diverges and activates cardiomyocyte proliferation signals, along with CPs from the hemogenic endothelium, epicardial, cardiopulmonary, and cardiac neural crest (CNC) lineages, to produce new cardiomyocytes (1,(6)(7)(8)(9)(10)(11). Gauging the relative contribution of each lineage for scaling their cardiomyogenic-and consequently therapeutic-capacity is a challenge.…”

An emerging consensus on cardiac regeneration

“…Hence, the true extent to which these Sca-1 lineage–traced CPCs contribute new cardiomyocytes to the heart remains uncertain. Moreover, recent lineage-tracing studies using endothelial drivers of Cre recombinase showed at least transient expression of Sca-1 on perivascular cells that eventually became cardiomyocytes, suggesting that Sca-1–expressing cells in the heart may simply be endothelial progenitors 32 . Importantly, there is no orthologous counterpart of Sca-1 in humans, thereby precluding isolation and therapeutic strategies based on Sca-1 as a cellular marker in humans.…”

Murine Models Demonstrate Distinct Vasculogenic and Cardiomyogenic cKit + Lineages in the Heart

“…This inconsistency has been shown in previous studies, which variably support 18, 21, 29 or refute endothelial cell 16, 35 differentiation capacity of cKit cells. Similarly, most studies document that coronary endothelium-producing cells do not express cKit 37–39 .…”