Transcriptional reversion of cardiac myocyte fate during mammalian cardiac regeneration. Circ Res 2015 Feb 27;116(5):804-15
Date
12/06/2014Pubmed ID
25477501Pubmed Central ID
PMC4344930DOI
10.1161/CIRCRESAHA.116.304269Scopus ID
2-s2.0-84924367823 (requires institutional sign-in at Scopus site) 123 CitationsAbstract
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.
Author List
O'Meara CC, Wamstad JA, Gladstone RA, Fomovsky GM, Butty VL, Shrikumar A, Gannon JB, Boyer LA, Lee RTAuthor
Caitlin C. O'Meara PhD Associate Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Newborn
Cell Adhesion Molecules
Cell Cycle
Cell Dedifferentiation
Cell Differentiation
Cells, Cultured
Culture Media, Serum-Free
DNA Replication
Gene Expression Regulation, Developmental
Gene Regulatory Networks
Heart Ventricles
Interleukin-13
Interleukin-13 Receptor alpha1 Subunit
Interleukin-4 Receptor alpha Subunit
Mice
Muscle Development
Myocytes, Cardiac
RNA Interference
RNA, Small Interfering
Rats
Rats, Sprague-Dawley
Regeneration
STAT3 Transcription Factor
STAT6 Transcription Factor
Sequence Alignment
Transcription Factors
Transcription, Genetic
Transcriptome
