Genetic Lineage Tracing of Sca-1⁺ Cells Reveals Endothelial but Not Myogenic Contribution to the Murine Heart.

Abstract

The adult mammalian heart displays a cardiomyocyte turnover rate of ≈1%/y 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. Here we generated Ly6a gene-targeted mice containing either a constitutive or an inducible Cre recombinase to perform genetic lineage tracing of Sca-1⁺ cells in vivo. 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, with 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 with an inducible Ly6a-MerCreMer allele also revealed a preferential expansion of Sca-1 lineage-traced endothelial cells after MI injury in the mouse. 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.