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bioRxiv · 10.1101/2022.09.01.506186

Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation

Walters, H.·Troyanovskiy, K.·Yun, M. H.
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Abstract

Salamanders are able to regenerate their entire limbs throughout lifespan, through a process that involves significant modulation of cellular plasticity. Limb regeneration is accompanied by the induction of cellular senescence, a state of irreversible cell cycle arrest associated with profound non-cell-autonomous consequences. While traditionally associated with detrimental physiological effects, here we show that senescent cells enhance newt limb regeneration. Through a lineage tracing approach, we demonstrate that senescent cells promote dedifferentiation of mature muscle tissue to generate regenerative progenitors. In a paradigm of newt myotube dedifferentiation, we uncover that senescent cells promote myotube cell cycle re-entry and reversal of muscle identity via secreted factors. Transcriptomic profiling and loss of function approaches identify the FGF-ERK signalling axis as a critical mediator of senescence-induced muscle plasticity. While chronic senescence constrains muscle regeneration in physiological mammalian contexts, we thus highlight a beneficial role for cellular senescence as an important modulator of dedifferentiation, a key mechanism for regeneration of complex structures.

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Walters, H., Troyanovskiy, K., Yun, M. H.. 2022-09-02. Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation. https://doi.org/10.1101/2022.09.01.506186

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