Genetic Lineage Tracing of Sca-1+ Cells Reveals Endothelial but Not Myogenic Contribution to the Murine Heart [Original Research Article]

Background—The adult mammalian heart displays a cardiomyocyte turnover rate of ~1% per year throughout postnatal life and after injuries such as myocardial infarction (MI), but the question of which cell types drive this low level of new cardiomyocyte formation remains contentious. Cardiac-resident stem cells marked by stem cell antigen-1 (Sca-1, gene name Ly6a) have been proposed as an important source of cardiomyocyte renewal. However, the in vivo contribution of endogenous Sca-1+ cells to the heart at baseline or after MI has not been investigated. Methods—Here we generated Ly6a gene-targeted mice containing either a constitutive or inducible Cre recombinase to perform genetic lineage tracing of Sca-1+ cells in vivo. Results—We observed that the contribution of endogenous Sca-1+ cells to the cardiomyocyte population in the heart was <0.005% throughout all of cardiac development, aging or after MI. In contrast, Sca-1+ cells abundantly contributed to the cardiac vasculature in mice during physiological growth and in the post-MI heart during cardiac remodeling. Specifically, Sca-1 lineage-traced endothelial cells expanded postnatally in the mouse heart after birth and into adulthood. Moreover, pulse-labeling of Sca-1+ cells using an inducible Ly6a-MerCreMer allele also revealed a preferential expansion of Sca-1 lineage-traced endothelial cells following MI injury in the mouse.Conclusions—Cardiac-resident Sca-1+ cells are not significant contributors to cardiomyocyte renewal in vivo. However, cardiac Sca-1+ cells represent a subset of vascular endothelial cells that expand postnatally with enhanced responsiveness to pathological stress in vivo.