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

Author

Listed:
  • 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
    Australian Regenerative Medicine Institute & Systems Biology Institute Australia, 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
    The University of Melbourne)

  • Kimara L. Targoff

    (College of Physicians & Surgeons, Columbia University
    Columbia Stem Cell Initiative, Columbia University)

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.

Suggested Citation

  • Carmen Sena-Tomás & Angelika G. Aleman & Caitlin Ford & Akriti Varshney & Di Yao & Jamie K. Harrington & Leonor Saúde & Mirana Ramialison & Kimara L. Targoff, 2022. "Activation of Nkx2.5 transcriptional program is required for adult myocardial repair," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30468-4
    DOI: 10.1038/s41467-022-30468-4
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