title: Inhibition of notch1-dependent cardiomyogenesis leads to a dilated myopathy in the neonatal heart.
abstract: BACKGROUND
  Physiological hypertrophy in the developing heart has been considered the product of an increase in volume of preexisting fetal cardiomyocytes in the absence of myocyte formation.
  
  
  OBJECTIVE
  In this study, we tested whether the mouse heart at birth has a pool of cardiac stem cells (CSCs) that differentiate into myocytes contributing to the postnatal expansion of the parenchymal cell compartment.
  
  
  RESULTS
  We have found that the newborn heart contains a population of c-kit-positive CSCs that are lineage negative, self-renewing, and multipotent. CSCs express the Notch1 receptor and show the nuclear localization of its active fragment, N1ICD. In 60% of cases, N1ICD was coupled with the presence of Nkx2.5, indicating that the commitment of CSCs to the myocyte lineage is regulated by Notch1. Importantly, overexpression of N1ICD in neonatal CSCs significantly expanded the proportion of transit-amplifying myocytes. To establish whether these in vitro findings had a functional counterpart in vivo, the Notch pathway was blocked in newborn mice by administration of a gamma-secretase inhibitor. This intervention resulted in the development of a dilated myopathy and high mortality rates. Ventricular decompensation was characterized by a 62% reduction in amplifying myocytes, which resulted in a 54% decrease in myocyte number. After cessation of Notch blockade and recovery of myocyte regeneration, cardiac anatomy and function were largely restored.
  
  
  CONCLUSIONS
  Notch1 signaling is a critical determinant of CSC growth and differentiation; when this cascade of events is altered, cardiomyogenesis is impaired, physiological cardiac hypertrophy is prevented, and a life-threatening myopathy supervenes.
authors.affiliation: Department of Anesthesia, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. kaurbanek@partners.org
authors.forename: Konrad
authors.initials: K
authors.lastname: Urbanek
authors.forename: Mauricio Castro
authors.initials: MC
authors.lastname: Cabral-da-Silva
authors.forename: Noriko
authors.initials: N
authors.lastname: Ide-Iwata
authors.forename: Silvia
authors.initials: S
authors.lastname: Maestroni
authors.forename: Francesca
authors.initials: F
authors.lastname: Delucchi
authors.forename: Hanqiao
authors.initials: H
authors.lastname: Zheng
authors.forename: João
authors.initials: J
authors.lastname: Ferreira-Martins
authors.forename: Barbara
authors.initials: B
authors.lastname: Ogórek
authors.forename: Domenico
authors.initials: D
authors.lastname: D'Amario
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Zerbini
authors.forename: Marcello
authors.initials: M
authors.lastname: Rota
authors.forename: Toru
authors.initials: T
authors.lastname: Hosoda
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
authors.forename: Piero
authors.initials: P
authors.lastname: Anversa
authors.forename: Jan
authors.initials: J
authors.lastname: Kajstura
authors.forename: Annarosa
authors.initials: A
authors.lastname: Leri
mesh_terms: D000185:Actinin / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002196:Capillaries / Q000166:cytology / Q000502:physiology; D002311:Cardiomyopathy, Dilated / Q000209:etiology* / Q000503:physiopathology; D002454:Cell Differentiation; D002455:Cell Division; D006321:Heart / Q000254:growth & development; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology*; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000199:Actins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D051880:Receptors, Notch; D014157:Transcription Factors; D000185:Actinin