title: Transcriptional reversion of cardiac myocyte fate during mammalian cardiac regeneration.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: From the Harvard Stem Cell Institute, the Brigham Regenerative Medicine Center, and the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and the Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA (C.C.O.M., R.A.G., G.M.F., J.B.G., R.T.L.); and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (J.A.W., V.L.B., A.S., L.A.B.).
authors.forename: Caitlin C
authors.initials: CC
authors.lastname: O'Meara
authors.affiliation: From the Harvard Stem Cell Institute, the Brigham Regenerative Medicine Center, and the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and the Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA (C.C.O.M., R.A.G., G.M.F., J.B.G., R.T.L.); and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (J.A.W., V.L.B., A.S., L.A.B.).
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Wamstad
authors.affiliation: From the Harvard Stem Cell Institute, the Brigham Regenerative Medicine Center, and the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and the Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA (C.C.O.M., R.A.G., G.M.F., J.B.G., R.T.L.); and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (J.A.W., V.L.B., A.S., L.A.B.).
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Gladstone
authors.affiliation: From the Harvard Stem Cell Institute, the Brigham Regenerative Medicine Center, and the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and the Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA (C.C.O.M., R.A.G., G.M.F., J.B.G., R.T.L.); and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (J.A.W., V.L.B., A.S., L.A.B.).
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Fomovsky
authors.affiliation: From the Harvard Stem Cell Institute, the Brigham Regenerative Medicine Center, and the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and the Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA (C.C.O.M., R.A.G., G.M.F., J.B.G., R.T.L.); and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (J.A.W., V.L.B., A.S., L.A.B.).
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Butty
authors.affiliation: From the Harvard Stem Cell Institute, the Brigham Regenerative Medicine Center, and the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and the Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA (C.C.O.M., R.A.G., G.M.F., J.B.G., R.T.L.); and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (J.A.W., V.L.B., A.S., L.A.B.).
authors.forename: Avanti
authors.initials: A
authors.lastname: Shrikumar
authors.affiliation: From the Harvard Stem Cell Institute, the Brigham Regenerative Medicine Center, and the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and the Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA (C.C.O.M., R.A.G., G.M.F., J.B.G., R.T.L.); and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (J.A.W., V.L.B., A.S., L.A.B.).
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Gannon
authors.affiliation: From the Harvard Stem Cell Institute, the Brigham Regenerative Medicine Center, and the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and the Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA (C.C.O.M., R.A.G., G.M.F., J.B.G., R.T.L.); and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (J.A.W., V.L.B., A.S., L.A.B.). lboyer@mit.edu rlee@partners.org.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Boyer
authors.affiliation: From the Harvard Stem Cell Institute, the Brigham Regenerative Medicine Center, and the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and the Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA (C.C.O.M., R.A.G., G.M.F., J.B.G., R.T.L.); and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (J.A.W., V.L.B., A.S., L.A.B.). lboyer@mit.edu rlee@partners.org.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lee
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015815:Cell Adhesion Molecules / Q000502:physiology; D002453:Cell Cycle; D054337:Cell Dedifferentiation / Q000235:genetics; D002454:Cell Differentiation; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004261:DNA Replication; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D006352:Heart Ventricles / Q000166:cytology; D018793:Interleukin-13 / Q000494:pharmacology / Q000502:physiology; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000037:antagonists & inhibitors / Q000235:genetics; D053662:Interleukin-4 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D024510:Muscle Development; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology; D050800:STAT6 Transcription Factor / Q000502:physiology; D016415:Sequence Alignment; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: D015815:Cell Adhesion Molecules; D016895:Culture Media, Serum-Free; C508185:Il13ra1 protein, rat; C504001:Il4r protein, rat; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D053662:Interleukin-4 Receptor alpha Subunit; C082838:Postn protein, mouse; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; C494087:Stat3 protein, mouse; C494100:Stat6 protein, mouse; D014157:Transcription Factors
keywords: cardiac myocyte; gene expression; growth factors/cytokines; myogenesis; regeneration