Inhibition of notch1-dependent cardiomyogenesis leads to a dilated myopathy in the neonatal heart.
BACKGROUND
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.


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 gamma-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.
Urbanek
Konrad
K
Department of Anesthesia, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. kaurbanek@partners.org
Cabral-da-Silva
Mauricio Castro
MC
Ide-Iwata
Noriko
N
Maestroni
Silvia
S
Delucchi
Francesca
F
Zheng
Hanqiao
H
Ferreira-Martins
João
J
Ogórek
Barbara
B
D'Amario
Domenico
D
Bauer
Michael
M
Zerbini
Gianpaolo
G
Rota
Marcello
M
Hosoda
Toru
T
Liao
Ronglih
R
Anversa
Piero
P
Kajstura
Jan
J
Leri
Annarosa
A
D000185:Actinin / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002196:Capillaries / Q000166:cytology / Q000502:physiology; D002311:Cardiomyopathy, Dilated / Q000209:etiology* / Q000503:physiopathology; D002454:Cell Differentiation; D002455:Cell Division; D006321:Heart / Q000254:growth & development; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology*; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism
D000199:Actins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D051880:Receptors, Notch; D014157:Transcription Factors; D000185:Actinin