Key result
AXL signaling drives cardiomyocyte dedifferentiation in mammals but fails to trigger cell cycle re-entry.
Why the study?
Cardiac injury outcomes vary widely across species from complete regeneration to irreversible scarring, prompting investigation into the cellular and molecular mechanisms of axolotl heart regeneration.
Does AXL signaling direct heart regeneration in axolotls and induce cardiomyocyte dedifferentiation in murine cardiomyocytes?
Does AXL signaling direct heart regeneration in axolotls and induce cardiomyocyte dedifferentiation in murine cardiomyocytes?
This preclinical study demonstrates that AXL signaling is essential for axolotl cardiac regeneration and induces mammalian cardiomyocyte dedifferentiation uncoupled from proliferation, offering mechanistic insight into cardiac cellular plasticity.
Answers are grounded in this paper and cite their sources.
May inform mammalian dedifferentiation research; leaves open translation to human cardiac regeneration.
Cardiac injury outcomes vary widely across species, from complete regeneration to irreversible scarring. Using single-nucleus multiomics and spatial transcriptomics, we generated a spatially resolved atlas of axolotl heart regeneration following injury, identifying a distinct border-zone cardiomyocyte population with a pro-regenerative transcriptional program. Ligand-receptor analysis of the border zone niche identified enrichment of the receptor tyrosine kinase AXL in injury-responsive cardiomyocytes and its ligand Gas6 in endothelial cells. Functional perturbation demonstrated AXL requirement for border-zone cardiomyocyte activation and axolotl heart regeneration. In murine cardiomyocytes, AXL overexpression induced sarcomere disassembly, metabolic rewiring, and immature gene expression without triggering proliferation. These findings show that AXL signaling induces cardiomyocyte dedifferentiation and uncouples dedifferentiation from cell cycle re-entry, providing mechanistic insight into cellular plasticity during heart regeneration.
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Bassat et al. (2025) studied Cardiac injury and heart regeneration. AXL signaling perturbation and overexpression was evaluated on Cardiomyocyte dedifferentiation and heart regeneration. AXL signaling is required for axolotl heart regeneration and induces mammalian cardiomyocyte dedifferentiation without triggering cell cycle re-entry.
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