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Cell Discov. 2019 Jun 4;5:30. doi: 10.1038/s41421-019-0095-9. eCollection 2019.

Single-cell imaging and transcriptomic analyses of endogenous cardiomyocyte dedifferentiation and cycling.

Zhang Y1,2,3, Gago-Lopez N1,2,3, Li N1,2,3,4, Zhang Z1,2,3, Alver N1,2,3, Liu Y1,2,3, Martinson AM2,3,5, Mehri A1,2,3, MacLellan WR1,2,3,6.

Author information

1Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA USA.
2Center for Cardiovascular Biology, University of Washington, Seattle, WA USA.
3Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA USA.
4State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China.
5Department of Pathology, University of Washington, Seattle, WA USA.
6Department of Bioengineering, University of Washington, Seattle, WA USA.


While it is recognized that there are low levels of new cardiomyocyte (CM) formation throughout life, the source of these new CM generates much debate. One hypothesis is that these new CMs arise from the proliferation of existing CMs potentially after dedifferentiation although direct evidence for this is lacking. Here we explore the mechanisms responsible for CM renewal in vivo using multi-reporter transgenic mouse models featuring efficient adult CM (ACM) genetic cell fate mapping and real-time cardiomyocyte lineage and dedifferentiation reporting. Our results demonstrate that non-myocytes (e.g., cardiac progenitor cells) contribute negligibly to new ACM formation at baseline or after cardiac injury. In contrast, we found a significant increase in dedifferentiated, cycling CMs in post-infarct hearts. ACM cell cycling was enhanced within the dedifferentiated CM population. Single-nucleus transcriptomic analysis demonstrated that CMs identified with dedifferentiation reporters had significant down-regulation in gene networks for cardiac hypertrophy, contractile, and electrical function, with shifts in metabolic pathways, but up-regulation in signaling pathways and gene sets for active cell cycle, proliferation, and cell survival. The results demonstrate that dedifferentiation may be an important prerequisite for CM proliferation and explain the limited but measurable cardiac myogenesis seen after myocardial infarction (MI).


Cell growth; Mechanisms of disease

Conflict of interest statement

Conflict of interestThe authors declare that they have no conflict of interest.

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