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STEM CELLS AND REGENERATION
β-Catenin drives distinct transcriptional networks in proliferative and nonproliferative cardiomyocytes
Gregory A. Quaife-Ryan, Richard J. Mills, George Lavers, Holly K. Voges, Celine J. Vivien, David A. Elliott, Mirana Ramialison, James E. Hudson, Enzo R. Porrello
Development 2020 147: dev193417 doi: 10.1242/dev.193417 Published 30 November 2020
Gregory A. Quaife-Ryan
1QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia
2School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
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Richard J. Mills
1QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia
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George Lavers
1QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia
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Holly K. Voges
3Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia
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Celine J. Vivien
3Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia
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David A. Elliott
3Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia
4Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia
5Department of Paediatrics, The Royal Children's Hospital, University of Melbourne, Parkville, Victoria 3052, Australia
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Mirana Ramialison
4Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia
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  • ORCID record for Mirana Ramialison
James E. Hudson
1QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia
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  • For correspondence: enzo.porrello@mcri.edu.au james.hudson@qimrberghofer.edu.au
Enzo R. Porrello
3Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia
6Department of Physiology, School of Biomedical Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
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  • For correspondence: enzo.porrello@mcri.edu.au james.hudson@qimrberghofer.edu.au

Handling Editor: Benoit Bruneau

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ABSTRACT

The inability of the adult mammalian heart to regenerate represents a fundamental barrier in heart failure management. By contrast, the neonatal heart retains a transient regenerative capacity, but the underlying mechanisms for the developmental loss of cardiac regenerative capacity in mammals are not fully understood. Wnt/β-catenin signalling has been proposed as a key cardioregenerative pathway driving cardiomyocyte proliferation. Here, we show that Wnt/β-catenin signalling potentiates neonatal mouse cardiomyocyte proliferation in vivo and immature human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) proliferation in vitro. By contrast, Wnt/β-catenin signalling in adult mice is cardioprotective but fails to induce cardiomyocyte proliferation. Transcriptional profiling and chromatin immunoprecipitation sequencing of neonatal mouse and hPSC-CMs revealed a core Wnt/β-catenin-dependent transcriptional network governing cardiomyocyte proliferation. By contrast, β-catenin failed to re-engage this neonatal proliferative gene network in the adult heart despite partial transcriptional re-activation of a neonatal glycolytic gene programme. These findings suggest that β-catenin might be repurposed from regenerative to protective functions in the adult heart in a developmental process dependent on the metabolic status of cardiomyocytes.

Footnotes

  • Competing interests

    G.A.Q.-R., R.J.M., J.E.H. and E.R.P. are co-inventors on patents for hCO maturation and cardiac regeneration held by The University of Queensland and QIMR Berghofer Medical Research Institute. J.E.H. is a co-inventor on licensed patents held by the University of Goettingen. R.J.M., E.R.P. and J.E.H. are co-founders, scientific advisors and stockholders in Dynomics.

  • Author contributions

    Conceptualization: G.A.Q.-R., J.E.H., E.R.P.; Methodology: G.A.Q.-R., C.J.V., D.A.E., M.R.; Formal analysis: G.A.Q.-R., R.J.M., G.L., H.K.V., J.E.H., E.R.P.; Investigation: G.A.Q.-R., R.J.M., G.L., H.K.V., C.J.V., J.E.H., E.R.P.; Resources: D.A.E.; Data curation: G.A.Q.-R., G.L., H.K.V., J.E.H.; Writing - original draft: G.A.Q.-R., J.E.H., E.R.P.; Writing - review & editing: G.A.Q.-R., R.J.M., C.J.V., D.A.E., J.E.H., E.R.P.; Supervision: M.R., J.E.H., E.R.P.; Project administration: J.E.H., E.R.P.; Funding acquisition: J.E.H., E.R.P.

  • Funding

    J.E.H. and E.R.P. acknowledge grant and fellowship support from the National Health and Medical Research Council of Australia, the Heart Foundation of Australia, the Stafford Fox Medical Research Foundation, Stem Cells Australia and QIMR Berghofer Medical Research Institute. The Murdoch Children's Research Institute is supported by the Victorian Government's Operational Infrastructure Support Program.

  • Data availability

    The CHIR hPSC-CM RNA-seq, adult mouse caBCAT RNA-seq and TCF7L2 ChIP-seq datasets have been deposited in GEO under the accession number GSE150521.

  • Supplementary information

    Supplementary information available online at https://dev.biologists.org/lookup/doi/10.1242/dev.193417.supplemental

  • Received June 1, 2020.
  • Accepted October 18, 2020.
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Keywords

  • Cardiac regeneration
  • Cardiomyocyte proliferation
  • Metabolism
  • Transcriptional regulation
  • Wnt/β-catenin

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STEM CELLS AND REGENERATION
β-Catenin drives distinct transcriptional networks in proliferative and nonproliferative cardiomyocytes
Gregory A. Quaife-Ryan, Richard J. Mills, George Lavers, Holly K. Voges, Celine J. Vivien, David A. Elliott, Mirana Ramialison, James E. Hudson, Enzo R. Porrello
Development 2020 147: dev193417 doi: 10.1242/dev.193417 Published 30 November 2020
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STEM CELLS AND REGENERATION
β-Catenin drives distinct transcriptional networks in proliferative and nonproliferative cardiomyocytes
Gregory A. Quaife-Ryan, Richard J. Mills, George Lavers, Holly K. Voges, Celine J. Vivien, David A. Elliott, Mirana Ramialison, James E. Hudson, Enzo R. Porrello
Development 2020 147: dev193417 doi: 10.1242/dev.193417 Published 30 November 2020

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