Related Experiment Video
Updated: Feb 21, 2026
Induction of Endothelial Differentiation in Cardiac Progenitor Cells Under Low Serum Conditions
Published on: January 7, 2019
Pathologic Stimulus Determines Lineage Commitment of Cardiac C-kit+ Cells
Zhongming Chen1,2, Wuqiang Zhu1,3, Ingrid Bender1,2
1Department of Medicine, Cardiovascular Division, University of Minnesota, Minneapolis (Z.C., W.Z., I.B., W.G., I-Y.K., T.J.H., N.N., J.Z., D.J.G., J.H.v.B.).
Insights
Different pathological stimuli influence cardiac c-kit+ cell differentiation. The tumor suppressor p53 is key for c-kit+ cells to become cardiomyocytes, offering therapeutic potential.
Area of Science:
- Cardiovascular Biology
- Stem Cell Biology
- Regenerative Medicine
Background:
- Cardiac c-kit+ cells are under investigation for cardiac repair, but their in vivo differentiation pathways remain unclear.
- Existing research indicates limited contribution of endogenous cardiac c-kit+ cells to the adult cardiomyocyte population.
- Understanding how pathological conditions influence c-kit+ cell fate is crucial for therapeutic development.
Purpose of the Study:
- To investigate the differential effects of various pathological stimuli on the lineage differentiation of cardiac c-kit+ cells in vivo.
- To elucidate the molecular mechanisms, particularly the role of p53, in c-kit+ cell-mediated cardiomyocyte generation.
Main Methods:
- Utilized single-cell sequencing to analyze the heterogeneity of cardiac c-kit+ cells.
- Employed genetic lineage tracing to track the fate of c-kit+ cells under different pathological conditions.
- Manipulated p53 expression to assess its role in cardiomyocyte differentiation.
Main Results:
- Cardiac c-kit+ cells exhibit inherent heterogeneity, comprising vascular and mesenchymal subtypes.
- Pressure overload increased c-kit+-derived cardiomyocytes, endothelial cells, and fibroblasts.
- Doxorubicin-induced cardiotoxicity promoted cardiomyocyte differentiation from c-kit+ cells, mediated by p53 activation.
- p53 inhibition blocked doxorubicin-induced cardiomyocyte differentiation, while p53 stabilization enhanced it.
Conclusions:
- Pathological stimuli differentially regulate the in vivo cell fates of cardiac c-kit+ cells.
- The tumor suppressor p53 plays a critical role in enabling c-kit+ cells to differentiate into cardiomyocytes.
- Targeting p53 pathways may offer a strategy to enhance cardiomyocyte generation from c-kit+ cells for cardiac repair.
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.
