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

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 si...

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Autores principales: Singh, Bhairab N., Koyano-Nakagawa, Naoko, Gong, Wuming, Moskowitz, Ivan P., Weaver, Cyprian V., Braunlin, Elizabeth, Das, Satyabrata, van Berlo, Jop H., Garry, Mary G., Garry, Daniel J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
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Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185975/
https://www.ncbi.nlm.nih.gov/pubmed/30315164
http://dx.doi.org/10.1038/s41467-018-06617-z
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author Singh, Bhairab N.
Koyano-Nakagawa, Naoko
Gong, Wuming
Moskowitz, Ivan P.
Weaver, Cyprian V.
Braunlin, Elizabeth
Das, Satyabrata
van Berlo, Jop H.
Garry, Mary G.
Garry, Daniel J.
author_facet Singh, Bhairab N.
Koyano-Nakagawa, Naoko
Gong, Wuming
Moskowitz, Ivan P.
Weaver, Cyprian V.
Braunlin, Elizabeth
Das, Satyabrata
van Berlo, Jop H.
Garry, Mary G.
Garry, Daniel J.
author_sort Singh, Bhairab N.
collection PubMed
description 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.
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spelling pubmed-61859752018-10-15 A conserved HH-Gli1-Mycn network regulates heart regeneration from newt to human Singh, Bhairab N. Koyano-Nakagawa, Naoko Gong, Wuming Moskowitz, Ivan P. Weaver, Cyprian V. Braunlin, Elizabeth Das, Satyabrata van Berlo, Jop H. Garry, Mary G. Garry, Daniel J. Nat Commun Article 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. Nature Publishing Group UK 2018-10-12 /pmc/articles/PMC6185975/ /pubmed/30315164 http://dx.doi.org/10.1038/s41467-018-06617-z Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Singh, Bhairab N.
Koyano-Nakagawa, Naoko
Gong, Wuming
Moskowitz, Ivan P.
Weaver, Cyprian V.
Braunlin, Elizabeth
Das, Satyabrata
van Berlo, Jop H.
Garry, Mary G.
Garry, Daniel J.
A conserved HH-Gli1-Mycn network regulates heart regeneration from newt to human
title A conserved HH-Gli1-Mycn network regulates heart regeneration from newt to human
title_full A conserved HH-Gli1-Mycn network regulates heart regeneration from newt to human
title_fullStr A conserved HH-Gli1-Mycn network regulates heart regeneration from newt to human
title_full_unstemmed A conserved HH-Gli1-Mycn network regulates heart regeneration from newt to human
title_short A conserved HH-Gli1-Mycn network regulates heart regeneration from newt to human
title_sort conserved hh-gli1-mycn network regulates heart regeneration from newt to human
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185975/
https://www.ncbi.nlm.nih.gov/pubmed/30315164
http://dx.doi.org/10.1038/s41467-018-06617-z
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