Handling Editor: Benoit Bruneau
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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