title: Sympathetic Reinnervation Is Required for Mammalian Cardiac Regeneration.
abstract: BACKGROUND
  Although mammalian cardiac regeneration can occur in the neonatal period, the factors involved in this process remain to be established. Because tissue and limb regeneration require concurrent reinnervation by the peripheral nervous system, we hypothesized that cardiac regeneration also requires reinnervation.
  
  
  OBJECTIVE
  To test the hypothesis that reinnervation is required for innate neonatal cardiac regeneration.
  
  
  RESULTS
  We crossed a Wnt1-Cre transgenic mouse with a double-tandem Tomato reporter strain to identify neural crest-derived cell lineages including the peripheral autonomic nerves in the heart. This approach facilitated the precise visualization of subepicardial autonomic nerves in the ventricles using whole mount epifluorescence microscopy. After resection of the left ventricular apex in 2-day-old neonatal mice, sympathetic nerve structures, which envelop the heart under normal conditions, exhibited robust regrowth into the regenerating myocardium. Chemical sympathectomy inhibited sympathetic regrowth and subsequent cardiac regeneration after apical resection significantly (scar size as cross-sectional percentage of viable left ventricular myocardium, n=9; 0.87%±1.4% versus n=6; 14.05±4.4%; P<0.01).
  
  
  CONCLUSIONS
  These findings demonstrate that the profound regenerative capacity of the neonatal mammalian heart requires sympathetic innervation. As such, these data offer significant insights into an underlying basis for inadequate adult regeneration after myocardial infarction, a situation where nerve growth is hindered by age-related influences and scar tissue.
authors.affiliation: From the Interdisciplinary Stem Cell Institute (I.A.W., W.B., J.M.H.) Departments of Medicine (W.B., J.M.H.) and Molecular and Cellular Pharmacology (J.M.H.), University of Miami Miller School of Medicine, FL; and Department of Genetics, University of Georgia, Athens (J.G.).
authors.forename: Ian A
authors.initials: IA
authors.lastname: White
authors.affiliation: From the Interdisciplinary Stem Cell Institute (I.A.W., W.B., J.M.H.) Departments of Medicine (W.B., J.M.H.) and Molecular and Cellular Pharmacology (J.M.H.), University of Miami Miller School of Medicine, FL; and Department of Genetics, University of Georgia, Athens (J.G.).
authors.forename: Julie
authors.initials: J
authors.lastname: Gordon
authors.affiliation: From the Interdisciplinary Stem Cell Institute (I.A.W., W.B., J.M.H.) Departments of Medicine (W.B., J.M.H.) and Molecular and Cellular Pharmacology (J.M.H.), University of Miami Miller School of Medicine, FL; and Department of Genetics, University of Georgia, Athens (J.G.).
authors.forename: Wayne
authors.initials: W
authors.lastname: Balkan
authors.affiliation: From the Interdisciplinary Stem Cell Institute (I.A.W., W.B., J.M.H.) Departments of Medicine (W.B., J.M.H.) and Molecular and Cellular Pharmacology (J.M.H.), University of Miami Miller School of Medicine, FL; and Department of Genetics, University of Georgia, Athens (J.G.).
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D055511:CCN Intercellular Signaling Proteins / Q000235:genetics; D006321:Heart / Q000294:innervation* / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics
chemical_list: D055511:CCN Intercellular Signaling Proteins; C492067:CCN4 protein, mouse; D011518:Proto-Oncogene Proteins
keywords: mice, transgenic; myocardium; regeneration; sympathectomy; sympathetic nervous system