Notch1 regulates the fate of cardiac progenitor cells.
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.
Boni
Alessandro
A
Department of Anesthesia and Division of Cardiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Urbanek
Konrad
K
Nascimbene
Angelo
A
Hosoda
Toru
T
Zheng
Hanqiao
H
Delucchi
Francesca
F
Amano
Katsuya
K
Gonzalez
Arantxa
A
Vitale
Serena
S
Ojaimi
Caroline
C
Rizzi
Roberto
R
Bolli
Roberto
R
Yutzey
Katherine E
KE
Rota
Marcello
M
Kajstura
Jan
J
Anversa
Piero
P
Leri
Annarosa
A
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D006321:Heart; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051881:Receptor, Notch1 / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C484469:Nkx2-5 protein, mouse; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D014157:Transcription Factors