Abstract
SummaryAlthough the mammalian heart is one of the least regenerative organs in the body, recent evidence indicates that the myocardium undergoes a certain degree of renewal to maintain homeostasis during normal aging. However, the cellular origin of cardiomyocyte renewal has remained elusive due to lack of lineage tracing experiments focusing on putative adult cardiac precursor cells. We have generated triple-transgenic mice based on the tet-cre system to identify descendants of cells that have expressed the stem cell marker Sca1. We found a significant and lasting contribution of Sca1-derived cells to cardiomyocytes during normal aging. Ischemic damage and pressure overload resulted in increased differentiation of Sca1-derived cells to the different cell types present in the heart. Our results reveal a source of cells for cardiomyocyte renewal and provide a possible explanation for the limited contribution of Sca1-derived cells to myocardial repair under pathological conditions.
Highlights
Proliferation of mammalian cardiomyocytes decreases after birth, eventually resulting in an arrest of cell division activity (Porrello et al, 2011), adult cardiomyocytes might enter the cell cycle under certain conditions and undergo endoreduplication (Rumyantsev et al, 1990)
The mammalian heart is one of the least regenerative organs in the body, recent evidence indicates that the myocardium undergoes a certain degree of renewal to maintain homeostasis during normal aging
The cellular origin of cardiomyocyte renewal has remained elusive due to lack of lineage tracing experiments focusing on putative adult cardiac precursor cells
Summary
Proliferation of mammalian cardiomyocytes decreases after birth, eventually resulting in an arrest of cell division activity (Porrello et al, 2011), adult cardiomyocytes might enter the cell cycle under certain conditions and undergo endoreduplication (Rumyantsev et al, 1990). Recent studies suggest that under normal physiological conditions, murine adult cardiomoycytes are able to give rise to new cardiomoycytes at a rate of $1.3%–4% per year (Malliaras et al, 2013), while pathological conditions seem to favor (limited) regeneration of the myocardium both by preexisting cardiomyocytes and by cardiac stem/progenitor cells (CSCs) (Senyo et al., 2013). Numerous attempts have been made to identify CSCs in the rodent heart, resulting in the identification of cell populations that express cell surface markers (e.g., C-KIT and SCA1 proteins), their long-term contribution to myocardial renewal is unknown due to the absence of cell-tracing studies (Parmacek and Epstein, 2009). We assess the fate of Sca1-positive cells in the myocardium using various cell lineage tracing approaches to analyze whether CSCs contribute to the turnover of cardiomyocytes during physiological aging and after myocardial injury
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