Transcriptional Reversion of Cardiac Myocyte Fate During Mammalian Cardiac Regeneration
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nihms647083.pdf
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Author(s)
O'Meara, C. C.
Gladstone, R. A.
Fomovsky, G. M.
Gannon, J. B.
Lee, R. T.
Wamstad, Joseph
Butty, Vincent L G
Shrikumar, A.
Boyer, Laurie Ann
Date Issued
December 2014
Journal
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer) -American Heart Association
Citation
O’Meara, C. C. et al. “Transcriptional Reversion of Cardiac Myocyte Fate During Mammalian Cardiac Regeneration.” Circulation Research 116, 5 (December 2014): 804–815 © 2014 American Heart Association, Inc
Version
Author's final manuscript
Abstract
Rationale: Neonatal mice have the capacity to regenerate their hearts in response to injury, but this potential is lost after the first week of life. The transcriptional changes that underpin mammalian cardiac regeneration have not been fully characterized at the molecular level. Objective: The objectives of our study were to determine whether myocytes revert the transcriptional phenotype to a less differentiated state during regeneration and to systematically interrogate the transcriptional data to identify and validate potential regulators of this process. Methods and Results: We derived a core transcriptional signature of injury-induced cardiac myocyte (CM) regeneration in mouse by comparing global transcriptional programs in a dynamic model of in vitro and in vivo CM differentiation, in vitro CM explant model, as well as a neonatal heart resection model. The regenerating mouse heart revealed a transcriptional reversion of CM differentiation processes, including reactivation of latent developmental programs similar to those observed during destabilization of a mature CM phenotype in the explant model. We identified potential upstream regulators of the core network, including interleukin 13, which induced CM cell cycle entry and STAT6/STAT3 signaling in vitro. We demonstrate that STAT3/periostin and STAT6 signaling are critical mediators of interleukin 13 signaling in CMs. These downstream signaling molecules are also modulated in the regenerating mouse heart. Conclusions: Our work reveals new insights into the transcriptional regulation of mammalian cardiac regeneration and provides the founding circuitry for identifying potential regulators for stimulating heart regeneration. Keywords: cardiac myocyte; gene expression; growth factors/cytokines; myogenesis regeneration
MIT Department
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1161/CIRCRESAHA.116.304269
