title: Neuregulin stimulation of cardiomyocyte regeneration in mice and human myocardium reveals a therapeutic window.
abstract: Therapies developed for adult patients with heart failure have been shown to be ineffective in pediatric clinical trials, leading to the recognition that new pediatric-specific therapies for heart failure must be developed. Administration of the recombinant growth factor neuregulin-1 (rNRG1) stimulates regeneration of heart muscle cells (cardiomyocytes) in adult mice. Because proliferation-competent cardiomyocytes are more abundant in growing mammals, we hypothesized that administration of rNRG1 during the neonatal period might be more effective than in adulthood. If so, neonatal rNRG1 delivery could be a new therapeutic strategy for treating heart failure in pediatric patients. To evaluate the effectiveness of rNRG1 administration in cardiac regeneration, newborn mice were subjected to cryoinjury, which induced myocardial dysfunction and scar formation and decreased cardiomyocyte cell cycle activity. Early administration of rNRG1 to mice from birth to 34 days of age improved myocardial function and reduced the prevalence of transmural scars. In contrast, administration of rNRG1 from 4 to 34 days of age only transiently improved myocardial function. The mechanisms of early administration involved cardiomyocyte protection (38%) and proliferation (62%). We also assessed the ability of rNRG1 to stimulate cardiomyocyte proliferation in intact cultured myocardium from pediatric patients. rNRG1 induced cardiomyocyte proliferation in myocardium from infants with heart disease who were less than 6 months of age. Our results identify an effective time period within which to execute rNRG1 clinical trials in pediatric patients for the stimulation of cardiomyocyte regeneration.
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, USA. Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Polizzotti
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, USA. Department of Pediatrics, University of Pittsburgh, and Richard King Mellon Institute for Pediatric Research and Division of Pediatric Cardiology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA.
authors.forename: Balakrishnan
authors.initials: B
authors.lastname: Ganapathy
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, USA. Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Walsh
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, USA. Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sangita
authors.initials: S
authors.lastname: Choudhury
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, USA. Department of Pediatrics, University of Pittsburgh, and Richard King Mellon Institute for Pediatric Research and Division of Pediatric Cardiology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA.
authors.forename: Niyatie
authors.initials: N
authors.lastname: Ammanamanchi
authors.affiliation: Preclinical MRI Core, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Bennett
authors.affiliation: Department of Anatomy, Bosch Institute, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Cristobal G
authors.initials: CG
authors.lastname: dos Remedios
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Haubner
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, USA. Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Department of Pediatrics, University of Pittsburgh, and Richard King Mellon Institute for Pediatric Research and Division of Pediatric Cardiology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA. Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, USA. bernhard.kuhn2@chp.edu.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kühn
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002318:Cardiovascular Diseases / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D002921:Cicatrix / Q000473:pathology; D003080:Cold Temperature; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007223:Infant; D051379:Mice; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology*; D020880:Neuregulins / Q000008:administration & dosage / Q000494:pharmacology*; D066247:Receptor, ErbB-4 / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects*
chemical_list: D020880:Neuregulins; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4
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