Pathologic Stimulus Determines Lineage Commitment of Cardiac C-kit+ Cellsopen access
- Authors
- Chen, Z.; Zhu, W.; Bender, I.; Gong, W.; Kwak, I.-Y.; Yellamilli, A.; Hodges, T.J.; Nemoto, N.; Zhang, J.; Garry, D.J.; van, Berlo J.H.
- Issue Date
- 2017
- Keywords
- adult stem cells; anthracyclines; c-kit; heart failure; regeneration
- Citation
- Circulation, v.136, no.24, pp 2359 - 2372
- Pages
- 14
- Journal Title
- Circulation
- Volume
- 136
- Number
- 24
- Start Page
- 2359
- End Page
- 2372
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/64067
- DOI
- 10.1161/CIRCULATIONAHA.117.030137
- ISSN
- 0009-7322
1524-4539
- 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. © 2017 American Heart Association, Inc.
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Collections - College of Business & Economics > Department of Applied Statistics > 1. Journal Articles
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