Inhibition of Notch1-Dependent Cardiomyogenesis Leads to a Dilated Myopathy in the Neonatal Heart

• Published in: Circulation research Vol. 107; no. 3; pp. 429 - 441
• Main Authors: Urbanek, Konrad, Cabral-da-Silva, Mauricio Castro, Ide-Iwata, Noriko, Maestroni, Silvia, Delucchi, Francesca, Zheng, Hanqiao, Ferreira-Martins, João, Ogórek, Barbara, DʼAmario, Domenico, Bauer, Michael, Zerbini, Gianpaolo, Rota, Marcello, Hosoda, Toru, Liao, Ronglih, Anversa, Piero, Kajstura, Jan, Leri, Annarosa
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 06-08-2010; Lippincott Williams & Wilkins
• Subjects: Actinin - metabolism; Actins - metabolism; Animals; Animals, Newborn; Biological and medical sciences; Capillaries - cytology; Capillaries - physiology; Cardiology. Vascular system; Cardiomyopathy, Dilated - etiology; Cardiomyopathy, Dilated - physiopathology; Cell Differentiation; Cell Division; Heart; Heart - growth & development; Humans; Infant, Newborn; Medical sciences; Mice; Myocarditis. Cardiomyopathies; Myocytes, Cardiac - cytology; Myocytes, Cardiac - physiology; Receptor, Notch1 - antagonists & inhibitors; Receptor, Notch1 - physiology; Receptors, Notch - antagonists & inhibitors; Receptors, Notch - physiology; Stem Cells - cytology; Stem Cells - physiology; Transcription Factors - metabolism; Heart; Animal model; Neonatal; Cardiomyopathy; Growth; Stem cell; Rodentia; Cardiovascular disease; cardiac stem cells; inhibition of myocyte growth; Myocardial disease; Organogenesis; Vertebrata; Mammalia; Mouse; Notch1; Heart disease; Newborn animal; Cardiomyocyte; Inhibition; Hypertrophy
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.110.218487

RATIONALEPhysiological 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.
OBJECTIVEIn 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.
METHODS AND RESULTSWe 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 γ-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.
CONCLUSIONSNotch1 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.