1. Notchi regulates the fate of cardiac progenitor cells.
- Author
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Boni, Alessandro, Urbanek, Konrad, Nascimbene, Angelo, Hosoda, Toru, Hanqiao Zheng, Delucchi, Francesca, Amano, Katsuya, Gonzalez, Arantxa, Vitale, Serena, Ojaimi, Caroline, Rizzi, Roberto, Bolli, Roberto, Yutzey, Katherine E., Rota, Marcello, Kajstura, Jan, Anversa, Piero, and Lenti, Annarosa
- Subjects
NOTCH genes ,HEART diseases ,CELL determination ,MUSCLE cells ,HOMEOSTASIS ,PHENOTYPES ,TRANSCRIPTION factors ,PATHOLOGY - 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 Notchi and raised the possibility that Notchi regulates myocyte commitment in the adult heart. Cardiac progenitor cells (CPC5) in the niches express Notch 1 receptor, and the supporting cells exhibit the Notch ligand Jaggedi. The nuclear translocation of Notchi intracellular domain (N1ICD) up-regulates Nkx2.5 in CPC5 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 Jaggedi activation of the Notch1 pathway. Importantly, inhibition of Notchi in infarcted mice impairs the commitment of resident CPC5 to the myocyte lineage opposing cardiomyogenesis. These observations indicate that Notchl favors the early specification of CPC5 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, Notchi may have critical implications in the control of heart homeostasis and its adaptation to pathologic states. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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