A conserved HH-Gli1-Mycn network regulates heart regeneration from newt to human

Bhairab N. Singh, Naoko Koyano-Nakagawa, Wuming Gong, Ivan P. Moskowitz, Cyprian V. Weaver, Elizabeth Braunlin, Satyabrata Das, Jop H. Berlo, Mary G. Garry () and Daniel J. Garry ()
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Bhairab N. Singh: University of Minnesota
Naoko Koyano-Nakagawa: University of Minnesota
Wuming Gong: University of Minnesota
Ivan P. Moskowitz: University of Chicago
Cyprian V. Weaver: University of Minnesota
Elizabeth Braunlin: University of Minnesota
Satyabrata Das: University of Minnesota
Jop H. Berlo: University of Minnesota
Mary G. Garry: University of Minnesota
Daniel J. Garry: University of Minnesota

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: Abstract The mammalian heart has a limited regenerative capacity and typically progresses to heart failure following injury. Here, we defined a hedgehog (HH)-Gli1-Mycn network for cardiomyocyte proliferation and heart regeneration from amphibians to mammals. Using a genome-wide screen, we verified that HH signaling was essential for heart regeneration in the injured newt. Next, pharmacological and genetic loss- and gain-of-function of HH signaling demonstrated the essential requirement for HH signaling in the neonatal, adolescent, and adult mouse heart regeneration, and in the proliferation of hiPSC-derived cardiomyocytes. Fate-mapping and molecular biological studies revealed that HH signaling, via a HH-Gli1-Mycn network, contributed to heart regeneration by inducing proliferation of pre-existing cardiomyocytes and not by de novo cardiomyogenesis. Further, Mycn mRNA transfection experiments recapitulated the effects of HH signaling and promoted adult cardiomyocyte proliferation. These studies defined an evolutionarily conserved function of HH signaling that may serve as a platform for human regenerative therapies.

Date: 2018
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DOI: 10.1038/s41467-018-06617-z

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