Beschreibung:
<jats:p>Cardiac regeneration is partly regulated by c‐kit<jats:sup>+</jats:sup> cardiac progenitor cells (CPC). Doxorubicin (DOX) is an effective anticancer chemotherapeutic which induces cardiotoxicity. To what extent c‐kit<jats:sup>+</jats:sup> CPCs are activated in response to DOX treatment and their fate remains unknown. Here, we used the following genetic mouse models to characterize the contribution of c‐kit<jats:sup>+</jats:sup> CPCs to cardiac repair mechanisms after DOX; c‐kit Cre‐IRES‐GFP mice to mark all cells that currently express the kit locus, c‐kit MerCreMer(MCM) cross‐bred to R26‐GFP reporter mice to mark CPC derived cells using inducible genetic lineage tracing, and c‐kit MCM cross‐bred to R26‐mT/mG double fluorescent reporter mice to differentiate de novo cardiomyocyte from cell fusion. Two‐month‐old mice were treated with DOX (20 mg/kg cumulative dose). Echocardiography one week after DOX injection showed significantly depressed cardiac function accompanied by cardiomyocyte apoptosis using immunohistochemistry for cleaved caspase 3. Furthermore, DOX activates expression of GATA4 specifically in CPCs. Presumably as a consequence of increased Gata4 expression, genetic lineage tracing of CPCs showed a significant increase (25‐fold) in cardiomyocyte formation, mostly newly formed. Interestingly, this was not at the expense of endothelial fate commitment. In conclusion, DOX enhances c‐kit<jats:sup>+</jats:sup> CPC cardiomyocyte commitment and differentiation. We are currently unraveling the underlying molecular pathways to enhance the myogenic potential of c‐kit<jats:sup>+</jats:sup> CPCs to repair injured hearts.</jats:p>