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

Zhongming Chen, Wuqiang Zhu, Ingrid Bender, Wuming Gong, Il Youp Kwak, Amritha Yellamilli, Thomas J. Hodges, Natsumi Nemoto, Jianyi Zhang, Daniel J. Garry, Jop H. van Berlo

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2359-2372
Number of pages14
JournalCirculation
Volume136
Issue number24
DOIs
StatePublished - Dec 12 2017

Keywords

  • adult stem cells
  • anthracyclines
  • c-kit
  • heart failure
  • regeneration

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