L'attivazione di Notch1 favorisce il differenziamento dei Progenitori Cardiaci in miociti

The Notch pathway mediates cell fate decision in multiple organs by regulating the expression of transcription factors that control cell differentiation. In the current work we tested the hypothesis that Nkx2.5 is a target gene of Notch1 and thereby regulates myocyte commitment in the adult mouse heart. Cardiac progenitor cells (CPCs) in the niches express the Notch1 receptor and the supporting cells exhibit the Notch ligand Jagged1. In CPCs stimulated with Jagged1, Notch1 activation was coupled with the up-regulation of Nkx2.5 and the formation of cycling myocytes in vitro. The active form of Notch (NICD) and RBP-jk form a protein complex in CPCs that, in turn, binds to the promoter of the Nkx2.5 gene initiating transcription. The inhibition of Notch1 signaling in infracted mice impaired cardiomyogenesis. Conversely, the commitment of resident CPCs to myocytes that retained a high proliferative state was preserved in control animals. These results indicate that Notch1 activation favors the early commitment of CPCs to the myocyte lineage, but the expression of Nkx2.5 does not abrogate their ability to divide. Cycling Nkx2.5 positive myocytes correspond to transient amplifying cells that condition the replicative capacity of the heart in physiologic and pathologic states.