Sonic hedgehog signaling regulates the mammalian cardiac regenerative response

[Speaker] Hiroyuki Kawagishi:1
[Co-author] Jianhua Xiong:2, Toren Finkel:3
1:Department of Molecular Pharmacology, Shinshu University School of Medicine, Japan, 2:Center for Molecular Medicine, National Heart, Lung and Blood Institute/NIH, USA, 3:Aging Institute of UPMC and the University of Pittsburgh, USA

Certain organisms, including zebrafish, are capable of complete cardiac regeneration in response to injury. This response has also been observed in the newborn mouse, although in this case, the regenerative capacity is lost at approximately one week of age. The mechanisms regulating this short temporal window of cardiac regeneration in mice are not well understood. Here, we show that sonic hedgehog (Shh) signaling modulates the neonatal mouse regenerative response. In particular, we demonstrate that following apical resection of the heart on postnatal day 1 (P1), mice activate Shh ligand expression and downstream signaling, while this response is largely absent when surgery is performed on non-regenerative, postnatal day 7 (P7) pups. Furthermore, an enhanced cardiac regeneration response was detected in ptch heterozygous mice which have a genetically-induced increase in Shh signaling. We further show, that after injury, Shh ligand is produced in the myocardium by non-myocytes and appears to regulate cardiomyocyte proliferation, as well as the recruitment of monocytes/macrophages to the regenerating area. Finally, we demonstrate that small molecule activators of Shh signaling are effective in promoting heart regeneration. Together, these results implicate Shh signaling as a regulator of mammalian heart regeneration and suggest that modulating this pathway may lead to new potential therapies for cardiovascular diseases.

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