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Dev Cell. 2015 Aug 24;34(4):387-99. doi: 10.1016/j.devcel.2015.06.017. Epub 2015 Aug 6.

Nerves Regulate Cardiomyocyte Proliferation and Heart Regeneration.

Author information

1
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.
2
Department of Cell Biology and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
3
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.
4
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.
5
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.

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.

PMID:
26256209
PMCID:
PMC4550513
DOI:
10.1016/j.devcel.2015.06.017
[Indexed for MEDLINE]
Free PMC Article

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