Resident c-kit+ cells in the heart are not cardiac stem cells

Abstract

Identifying a bona fide population of cardiac stem cells (CSCs) is a critical step for developing cell-based therapies for heart failure patients. Previously, cardiac c-kit+ cells were reported to be CSCs with a potential to become myocardial, endothelial and smooth muscle cells in vitro and after cardiac injury. Here we provide further insights into the nature of cardiac c-kit+ cells. By targeting the c-kit locus with multiple reporter genes in mice, we find that c-kit expression rarely co-localizes with the expression of the cardiac progenitor and myogenic marker Nkx2.5, or that of the myocardial marker, cardiac troponin T (cTnT). Instead, c-kit predominantly labels a cardiac endothelial cell population in developing and adult hearts. After acute cardiac injury, c-kit+ cells retain their endothelial identity and do not become myogenic progenitors or cardiomyocytes. Thus, our work strongly suggests that c-kit+ cells in the murine heart are endothelial cells and not CSCs.

Preconditioning c-Kit-positive Human Cardiac Stem Cells with a Nitric Oxide Donor Enhances Cell Survival through Activation of Survival Signaling Pathways

“…A study by Molkentin and coworkers (71) has shown that c-Kit ϩ cells minimally contribute to cardiomyogenesis but amply generate cardiac endothelial cells. A genetic c-Kit lineage tracing study from another laboratory has also shown that these c-Kit ϩ cells exhibit endothelial markers (72). These results suggest that the proportion of cardiomyocytes derived from c-Kit ϩ cells are limited.…”

Preexisting endothelial cells mediate cardiac neovascularization after injury

“…One may ask whether cardiac stem cells such as Kit + cells, Sca1 + cells, or epicardial progenitors contribute to new coronary endothelial cells after cardiac injury. As for Kit + cells, genetic-lineage-tracing studies showed that Kit-Cre labels a substantial number of endothelial cells in the normal heart and that those cells expand to generate more coronary endothelial cells after injury (40)(41)(42) (43), and lineage-tracing studies show that Sca1-derived cells are most endothelial cells in the normal heart (44). Our endothelial cell-tracing study suggests that these Sca1 + endothelial cells might expand after injury and that Sca1 + nonendothelial cells minimally contributed to coronary endothelial cells.…”

Developmental origin and lineage plasticity of endogenous cardiac stem cells

“…Attempting to shed light on these issues, Cai and Zhou and colleagues recently reported the generation of more sensitive knock-in alleles inserting conditional CRE and/or marker cassettes directly into the ATG start codon of the first Kit coding exon (Liu et al, 2016;Sultana et al, 2015). With these tools, in contrast to previous studies, KIT + cells were found to be abundant in fetal hearts and throughout postnatal life into adulthood.…”