Abstract 1449: Notch-1 Signaling Regulates Postnatal Cardiomyocyte Proliferation
INTRODUCTION The identification of the molecular mechanisms controlling cardiomyocyte proliferation during the embryonic and early neonatal life appears of paramount interest with a view to exploiting this information to promote cardiac regeneration in adults. The Notch signaling pathway finely tunes the balance between proliferation and differentiation of stem and progenitor cells in several different settings, including hematopoietic, nervous and heart tissues.
HYPOTHESIS Given the role of the Notch pathway in preserving progenitor cell pools in several systems, we assessed the possibility that the proliferative potential of immature, still proliferating cardiomyocytes (ICMs) could rely on Notch1 activity and that the forced activation of this pathway might lead to ICMs expansion.
METHODS Primary cultures of rat neonatal cardiomyocytes were used as a model to investigate the role of Notch in regulating their proliferation. Inhibition of Notch signaling was triggered by γ-secretase inhibitors; stimulation was triggered either by culturing freshly isolated cardiomyocytes in the presence of a soluble form of Jagged1 (sJ1) or by the constitutive expression of activated Notch1 using an Adeno-Associated Virus.
RESULTS We found that Notch1 is highly expressed in proliferating ICMs both in vitro and in vivo, and that the number of Notch-positive cells in the heart declines with age. Notch1 expression in ICMs paralleled that of its cognate Jagged1 ligand on stromal supporting cells. The inhibition of Notch signaling in ICMs blocked their proliferation and induced apoptosis; in contrast, its activation by Jagged1 or by the constitutive expression of its activated form markedly stimulated proliferative signaling and promoted ICM expansion.
CONCLUSIONS These results provide strong evidence that immature, still proliferating cardiomyocytes rely on Notch1 activity for their renewal, indicating that the forced activation of this pathway might lead to the expansion of the pool of undifferentiated, committed cardiac progenitor cells. Maintenance or re-activation of Notch signaling in cardiac myocytes might thus represent an exciting target for innovative regenerative therapy.