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

Carmen Sena-Tomás, Angelika G. Aleman, Caitlin Ford, Akriti Varshney, Di Yao, Jamie K. Harrington, Leonor Saúde, Mirana Ramialison and Kimara L. Targoff ()
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Carmen Sena-Tomás: College of Physicians & Surgeons, Columbia University
Angelika G. Aleman: College of Physicians & Surgeons, Columbia University
Caitlin Ford: College of Physicians & Surgeons, Columbia University
Akriti Varshney: Monash University
Di Yao: College of Physicians & Surgeons, Columbia University
Jamie K. Harrington: College of Physicians & Surgeons, Columbia University
Leonor Saúde: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa
Mirana Ramialison: Australian Regenerative Medicine Institute & Systems Biology Institute Australia, Monash University
Kimara L. Targoff: College of Physicians & Surgeons, Columbia University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-30468-4

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