Unknown

Dataset Information

0

Pathologic Stimulus Determines Lineage Commitment of Cardiac C-kit+ Cells.


ABSTRACT: BACKGROUND:Although cardiac c-kit+ cells are being tested in clinical trials, the circumstances that determine lineage differentiation of c-kit+ cells in vivo are unknown. Recent findings suggest that endogenous cardiac c-kit+ cells rarely contribute cardiomyocytes to the adult heart. We assessed whether various pathological stimuli differentially affect the eventual cell fates of c-kit+ cells. METHODS:We used single-cell sequencing and genetic lineage tracing of c-kit+ cells to determine whether various pathological stimuli would result in different fates of c-kit+ cells. RESULTS:Single-cell sequencing of cardiac CD45-c-kit+ cells showed innate heterogeneity, indicative of the existence of vascular and mesenchymal c-kit+ cells in normal hearts. Cardiac pressure overload resulted in a modest increase in c-kit-derived cardiomyocytes, with significant increases in the numbers of endothelial cells and fibroblasts. Doxorubicin-induced acute cardiotoxicity did not increase c-kit-derived endothelial cell fates but instead induced cardiomyocyte differentiation. Mechanistically, doxorubicin-induced DNA damage in c-kit+ cells resulted in expression of p53. Inhibition of p53 blocked cardiomyocyte differentiation in response to doxorubicin, whereas stabilization of p53 was sufficient to increase c-kit-derived cardiomyocyte differentiation. CONCLUSIONS:These results demonstrate that different pathological stimuli induce different cell fates of c-kit+ cells in vivo. Although the overall rate of cardiomyocyte formation from c-kit+ cells is still below clinically relevant levels, we show that p53 is central to the ability of c-kit+ cells to adopt cardiomyocyte fates, which could lead to the development of strategies to preferentially generate cardiomyocytes from c-kit+ cells.

SUBMITTER: Chen Z 

PROVIDER: S-EPMC5726921 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

altmetric image

Publications


<h4>Background</h4>Although cardiac c-kit<sup>+</sup> cells are being tested in clinical trials, the circumstances that determine lineage differentiation of c-kit<sup>+</sup> cells in vivo are unknown. Recent findings suggest that endogenous cardiac c-kit<sup>+</sup> cells rarely contribute cardiomyocytes to the adult heart. We assessed whether various pathological stimuli differentially affect the eventual cell fates of c-kit<sup>+</sup> cells.<h4>Methods</h4>We used single-cell sequencing and  ...[more]

Similar Datasets

| S-EPMC6709597 | biostudies-literature
| S-EPMC10544823 | biostudies-literature
| S-EPMC6588544 | biostudies-literature
| S-EPMC5929163 | biostudies-literature
| S-EPMC8172824 | biostudies-literature
| S-EPMC5247458 | biostudies-literature
| S-EPMC6156395 | biostudies-literature
| S-EPMC4618046 | biostudies-literature
| S-EPMC6916193 | biostudies-literature
| S-EPMC5386384 | biostudies-literature