Inhibition of Notch1-dependent cardiomyogenesis leads to a dilated myopathy in the neonatal heart

Konrad Urbanek, Mauricio Castro Cabral-Da-Silva, Noriko Ide-Iwata, Silvia Maestroni, Francesca Delucchi, Hanqiao Zheng, João Ferreira-Martins, Barbara Ogórek, Domenico D'Amario, Michael Bauer, Gianpaolo Zerbini, Marcello Rota, Toru Hosoda, Ronglih Liao, Piero Anversa, Jan Kajstura, Annarosa Leri

Research output: Contribution to journalArticle

Abstract

Rationale: 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. Methods and 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 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. 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.

Original languageEnglish
Pages (from-to)429-441
Number of pages13
JournalCirculation Research
Volume107
Issue number3
DOIs
Publication statusPublished - Aug 6 2010

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Keywords

  • Cardiac stem cells
  • Inhibition of myocyte growth
  • Notch1

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Urbanek, K., Cabral-Da-Silva, M. C., Ide-Iwata, N., Maestroni, S., Delucchi, F., Zheng, H., Ferreira-Martins, J., Ogórek, B., D'Amario, D., Bauer, M., Zerbini, G., Rota, M., Hosoda, T., Liao, R., Anversa, P., Kajstura, J., & Leri, A. (2010). Inhibition of Notch1-dependent cardiomyogenesis leads to a dilated myopathy in the neonatal heart. Circulation Research, 107(3), 429-441. https://doi.org/10.1161/CIRCRESAHA.110.218487