title: Nerves Regulate Cardiomyocyte Proliferation and Heart Regeneration.
abstract: Some organisms, such as adult zebrafish and newborn mice, have the capacity to regenerate heart tissue following injury. Unraveling the mechanisms of heart regeneration is fundamental to understanding why regeneration fails in adult humans. Numerous studies have revealed that nerves are crucial for organ regeneration, thus we aimed to determine whether nerves guide heart regeneration. Here, we show using transgenic zebrafish that inhibition of cardiac innervation leads to reduction of myocyte proliferation following injury. Specifically, pharmacological inhibition of cholinergic nerve function reduces cardiomyocyte proliferation in the injured hearts of both zebrafish and neonatal mice. Direct mechanical denervation impairs heart regeneration in neonatal mice, which was rescued by the administration of neuregulin 1 (NRG1) and nerve growth factor (NGF) recombinant proteins. Transcriptional analysis of mechanically denervated hearts revealed a blunted inflammatory and immune response following injury. These findings demonstrate that nerve function is required for both zebrafish and mouse heart regeneration.
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, and the Brigham Regenerative Medicine Center, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02139, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ahmed I
authors.initials: AI
authors.lastname: Mahmoud
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, and the Brigham Regenerative Medicine Center, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02139, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Caitlin C
authors.initials: CC
authors.lastname: O'Meara
authors.affiliation: Department of Cell Biology and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gemberling
authors.affiliation: Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Long
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, and the Brigham Regenerative Medicine Center, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02139, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bryant
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, and the Brigham Regenerative Medicine Center, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02139, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ruimao
authors.initials: R
authors.lastname: Zheng
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, and the Brigham Regenerative Medicine Center, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02139, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Gannon
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, and the Brigham Regenerative Medicine Center, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02139, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Cai
authors.affiliation: Department of Cell Biology and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Wen-Yee
authors.initials: WY
authors.lastname: Choi
authors.affiliation: Department of Cell Biology and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Egnaczyk
authors.affiliation: Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Burns
authors.affiliation: Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Burns
authors.affiliation: Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Calum A
authors.initials: CA
authors.lastname: MacRae
authors.affiliation: Department of Cell Biology and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Poss
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, and the Brigham Regenerative Medicine Center, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02139, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: rlee@partners.org.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lee
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D049109:Cell Proliferation / Q000187:drug effects; D059329:Cholinergic Neurons / Q000502:physiology*; D003714:Denervation; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000294:innervation* / Q000502:physiology*; D007109:Immunity / Q000187:drug effects / Q000235:genetics; D007249:Inflammation / Q000235:genetics; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000166:cytology*; D020932:Nerve Growth Factor / Q000494:pharmacology; D020890:Neuregulin-1 / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D014628:Vagotomy; D015027:Zebrafish
chemical_list: D020890:Neuregulin-1; D020932:Nerve Growth Factor