The inability of the adult mammalian heart to regenerate represents a fundamental barrier in heart failure management. In 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 signaling has been proposed as a key cardio-regenerative pathway driving cardiomyocyte proliferation. Here, we show that Wnt/β-catenin signaling potentiates neonatal mouse cardiomyocyte proliferation in vivo and immature human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) proliferation in vitro. In contrast, Wnt/β-catenin signaling in adult mice is cardioprotective but fails to induce cardiomyocyte proliferation. Transcriptional profiling and chromatin immunoprecipitation sequencing of neonatal mouse and hPSC-CM revealed a core Wnt/β-catenin-dependent transcriptional network governing cardiomyocyte proliferation. In 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 program. These findings suggest that β-catenin may be repurposed from regenerative to protective functions in the adult heart in a developmental process dependent on the metabolic status of cardiomyocytes.
β-catenin drives distinct transcriptional networks in proliferative and non-proliferative cardiomyocytes
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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; β-catenin drives distinct transcriptional networks in proliferative and non-proliferative cardiomyocytes. Development 2020; dev.193417. doi: https://doi.org/10.1242/dev.193417
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