TY - JOUR
T1 - Inhibition of Notch1-dependent cardiomyogenesis leads to a dilated myopathy in the neonatal heart
AU - Urbanek, Konrad
AU - Cabral-Da-Silva, Mauricio Castro
AU - Ide-Iwata, Noriko
AU - Maestroni, Silvia
AU - Delucchi, Francesca
AU - Zheng, Hanqiao
AU - Ferreira-Martins, João
AU - Ogórek, Barbara
AU - D'Amario, Domenico
AU - Bauer, Michael
AU - Zerbini, Gianpaolo
AU - Rota, Marcello
AU - Hosoda, Toru
AU - Liao, Ronglih
AU - Anversa, Piero
AU - Kajstura, Jan
AU - Leri, Annarosa
PY - 2010/8/6
Y1 - 2010/8/6
N2 - Rationale: 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. Methods and 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 γ-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.
AB - Rationale: 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. Methods and 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 γ-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.
KW - Cardiac stem cells
KW - Inhibition of myocyte growth
KW - Notch1
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U2 - 10.1161/CIRCRESAHA.110.218487
DO - 10.1161/CIRCRESAHA.110.218487
M3 - Article
C2 - 20558824
AN - SCOPUS:77956642774
VL - 107
SP - 429
EP - 441
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 3
ER -