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Activation of Nkx2.5 transcriptional program is required for adult myocardial repair

The cardiac developmental network has been associated with myocardial regenerative potential. However, the embryonic signals triggered following injury have yet to be fully elucidated. Nkx2.5 is a key causative transcription factor associated with human congenital heart disease and one of the earlie...

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Autores principales: de Sena-Tomás, Carmen, Aleman, Angelika G., Ford, Caitlin, Varshney, Akriti, Yao, Di, Harrington, Jamie K., Saúde, Leonor, Ramialison, Mirana, Targoff, Kimara L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9142600/
https://www.ncbi.nlm.nih.gov/pubmed/35624100
http://dx.doi.org/10.1038/s41467-022-30468-4
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author de Sena-Tomás, Carmen
Aleman, Angelika G.
Ford, Caitlin
Varshney, Akriti
Yao, Di
Harrington, Jamie K.
Saúde, Leonor
Ramialison, Mirana
Targoff, Kimara L.
author_facet de Sena-Tomás, Carmen
Aleman, Angelika G.
Ford, Caitlin
Varshney, Akriti
Yao, Di
Harrington, Jamie K.
Saúde, Leonor
Ramialison, Mirana
Targoff, Kimara L.
author_sort de Sena-Tomás, Carmen
collection PubMed
description The cardiac developmental network has been associated with myocardial regenerative potential. However, the embryonic signals triggered following injury have yet to be fully elucidated. Nkx2.5 is a key causative transcription factor associated with human congenital heart disease and one of the earliest markers of cardiac progenitors, thus it serves as a promising candidate. Here, we show that cardiac-specific RNA-sequencing studies reveal a disrupted embryonic transcriptional profile in the adult Nkx2.5 loss-of-function myocardium. nkx2.5(−/−) fish exhibit an impaired ability to recover following ventricular apex amputation with diminished dedifferentiation and proliferation. Complex network analyses illuminate that Nkx2.5 is required to provoke proteolytic pathways necessary for sarcomere disassembly and to mount a proliferative response for cardiomyocyte renewal. Moreover, Nkx2.5 targets embedded in these distinct gene regulatory modules coordinate appropriate, multi-faceted injury responses. Altogether, our findings support a previously unrecognized, Nkx2.5-dependent regenerative circuit that invokes myocardial cell cycle re-entry, proteolysis, and mitochondrial metabolism to ensure effective regeneration in the teleost heart.
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spelling pubmed-91426002022-05-29 Activation of Nkx2.5 transcriptional program is required for adult myocardial repair de Sena-Tomás, Carmen Aleman, Angelika G. Ford, Caitlin Varshney, Akriti Yao, Di Harrington, Jamie K. Saúde, Leonor Ramialison, Mirana Targoff, Kimara L. Nat Commun Article The cardiac developmental network has been associated with myocardial regenerative potential. However, the embryonic signals triggered following injury have yet to be fully elucidated. Nkx2.5 is a key causative transcription factor associated with human congenital heart disease and one of the earliest markers of cardiac progenitors, thus it serves as a promising candidate. Here, we show that cardiac-specific RNA-sequencing studies reveal a disrupted embryonic transcriptional profile in the adult Nkx2.5 loss-of-function myocardium. nkx2.5(−/−) fish exhibit an impaired ability to recover following ventricular apex amputation with diminished dedifferentiation and proliferation. Complex network analyses illuminate that Nkx2.5 is required to provoke proteolytic pathways necessary for sarcomere disassembly and to mount a proliferative response for cardiomyocyte renewal. Moreover, Nkx2.5 targets embedded in these distinct gene regulatory modules coordinate appropriate, multi-faceted injury responses. Altogether, our findings support a previously unrecognized, Nkx2.5-dependent regenerative circuit that invokes myocardial cell cycle re-entry, proteolysis, and mitochondrial metabolism to ensure effective regeneration in the teleost heart. Nature Publishing Group UK 2022-05-27 /pmc/articles/PMC9142600/ /pubmed/35624100 http://dx.doi.org/10.1038/s41467-022-30468-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
de Sena-Tomás, Carmen
Aleman, Angelika G.
Ford, Caitlin
Varshney, Akriti
Yao, Di
Harrington, Jamie K.
Saúde, Leonor
Ramialison, Mirana
Targoff, Kimara L.
Activation of Nkx2.5 transcriptional program is required for adult myocardial repair
title Activation of Nkx2.5 transcriptional program is required for adult myocardial repair
title_full Activation of Nkx2.5 transcriptional program is required for adult myocardial repair
title_fullStr Activation of Nkx2.5 transcriptional program is required for adult myocardial repair
title_full_unstemmed Activation of Nkx2.5 transcriptional program is required for adult myocardial repair
title_short Activation of Nkx2.5 transcriptional program is required for adult myocardial repair
title_sort activation of nkx2.5 transcriptional program is required for adult myocardial repair
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9142600/
https://www.ncbi.nlm.nih.gov/pubmed/35624100
http://dx.doi.org/10.1038/s41467-022-30468-4
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