Notch1 regulates the fate of cardiac progenitor cells

Alessandro Boni, Konrad Urbanek, Angelo Nascimbene, Toru Hosoda, Hanqiao Zheng, Francesca Delucchi, Katsuya Amano, Arantxa Gonzalez, Serena Vitale, Caroline Ojaimi, Roberto Rizzi, Roberto Bolli, Katherine E. Yutzey, Marcello Rota, Jan Kajstura, Piero Anversa, Annarosa Leri

Research output: Contribution to journalArticle

Abstract

The Notch receptor mediates cell fate decision in multiple organs. In the current work we tested the hypothesis that Nkx2.5 is a target gene of Notch1 and raised the possibility that Notch1 regulates myocyte commitment in the adult heart. Cardiac progenitor cells (CPCs) in the niches express Notch1 receptor, and the supporting cells exhibit the Notch ligand Jagged1. The nuclear translocation of Notch1 intracellular domain (N1ICD) up-regulates Nkx2.5 in CPCs and promotes the formation of cycling myocytes in vitro. N1ICD and RBP-Jk form a protein complex, which in turn binds to the Nkx2.5 promoter initiating transcription and myocyte differentiation. In contrast, transcription factors of vascular cells are down-regulated by Jagged1 activation of the Notch1 pathway. Importantly, inhibition of Notch1 in infarcted mice impairs the commitment of resident CPCs to the myocyte lineage opposing cardiomyogenesis. These observations indicate that Notch1 favors the early specification of CPCs to the myocyte phenotype but maintains the newly formed cells in a highly proliferative state. Dividing Nkx2.5-positive myocytes correspond to transit amplifying cells, which condition the replicative capacity of the heart. In conclusion, Notch1 may have critical implications in the control of heart homeostasis and its adaptation to pathologic states.

Original languageEnglish
Pages (from-to)15529-15534
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number40
DOIs
Publication statusPublished - Oct 7 2008

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Keywords

  • Cardiac regeneration
  • Myocardial infarction

ASJC Scopus subject areas

  • General

Cite this

Boni, A., Urbanek, K., Nascimbene, A., Hosoda, T., Zheng, H., Delucchi, F., Amano, K., Gonzalez, A., Vitale, S., Ojaimi, C., Rizzi, R., Bolli, R., Yutzey, K. E., Rota, M., Kajstura, J., Anversa, P., & Leri, A. (2008). Notch1 regulates the fate of cardiac progenitor cells. Proceedings of the National Academy of Sciences of the United States of America, 105(40), 15529-15534. https://doi.org/10.1073/pnas.0808357105