Abstract 19135: Shh-hippo Signaling Pathway Controls Cardiomyocyte Proliferation
In contrast to newts and zebrafish, the mammalian heart has limited regenerative potential. Defining the molecular cues controlling cardiac regeneration/cellular proliferation would help construct a blueprint to enhance our understanding of cardiac regeneration in mammals. Here, we demonstrate the essential requirement of sonic hedgehog (Shh) signaling during newt heart regeneration and neonatal cardiomyocyte proliferation. In response to ventricular resection, Shh and its downstream effectors including Ptch1 and Smoothened (Smo) are robustly expressed in the injured region. We find that Shh signaling is required for the proliferation of both epicardial as well as myocardial cell types during the regenerative process. Our data indicate that newt cardiomyocytes undergo dedifferentiation in response to resection injury allowing proliferation, regeneration and restoration of cardiac function. Furthermore, pharmacogical inhibition of Shh signaling results in complete ablation of regeneration and subsequent scar formation. Similar to the newt heart, the activation of Shh signals in cultured neonatal cardiomyocytes (MVCMs) promotes cardiomyocyte proliferation, whereas inhibition results in markedly reduced proliferation. Molecular analyses indicate that activation of Shh signaling increases TAZ (a transcriptional co-activator of Hippo signaling) expression, while inhibition results in its reduction. Interestingly, the intracellular localization of TAZ is not altered upon modulation of Shh signaling. These data suggest that the effect of Shh signals on proliferation is mediated through the TAZ-hippo signaling pathway. Our findings demonstrate that the Shh-Hippo signaling pathways function as a key regulator of cardiomyocyte proliferation and potential targets for cardiac regenerative therapies.
- © 2013 by American Heart Association, Inc.