title: Epigenomic Reprogramming of Adult Cardiomyocyte-Derived Cardiac Progenitor Cells.
abstract: It has been believed that mammalian adult cardiomyocytes (ACMs) are terminally-differentiated and are unable to proliferate. Recently, using a bi-transgenic ACM fate mapping mouse model and an in vitro culture system, we demonstrated that adult mouse cardiomyocytes were able to dedifferentiate into cardiac progenitor-like cells (CPCs). However, little is known about the molecular basis of their intrinsic cellular plasticity. Here we integrate single-cell transcriptome and whole-genome DNA methylation analyses to unravel the molecular mechanisms underlying the dedifferentiation and cell cycle reentry of mouse ACMs. Compared to parental cardiomyocytes, dedifferentiated mouse cardiomyocyte-derived CPCs (mCPCs) display epigenomic reprogramming with many differentially-methylated regions, both hypermethylated and hypomethylated, across the entire genome. Correlated well with the methylome, our transcriptomic data showed that the genes encoding cardiac structure and function proteins are remarkably down-regulated in mCPCs, while those for cell cycle, proliferation, and stemness are significantly up-regulated. In addition, implantation of mCPCs into infarcted mouse myocardium improves cardiac function with augmented left ventricular ejection fraction. Our study demonstrates that the cellular plasticity of mammalian cardiomyocytes is the result of a well-orchestrated epigenomic reprogramming and a subsequent global transcriptomic alteration.
authors.affiliation: Division of Cardiology, Department of Medicine, and Center for Cardiovascular Biology, and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.|The Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Ostrow School of Dentistry and Department of Pediatrics, School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Jiang F
authors.initials: JF
authors.lastname: Zhong
authors.affiliation: Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Qiu
authors.affiliation: Division of Cardiology, Department of Medicine, and Center for Cardiovascular Biology, and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.
authors.forename: W Robb
authors.initials: WR
authors.lastname: MacLellan
authors.affiliation: The Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
authors.affiliation: Center for Genomics &Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92350, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Wang
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation / Q000235:genetics*; D065150:Cellular Reprogramming; D000067470:Cellular Reprogramming Techniques; D016000:Cluster Analysis; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D057890:Epigenomics; D020869:Gene Expression Profiling; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D032386:Myoblasts, Cardiac / Q000166:cytology* / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D015203:Reproducibility of Results; D059010:Single-Cell Analysis; D033581:Stem Cell Transplantation; D059467:Transcriptome