Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation

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 endogenous 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 can enhance newt limb regeneration. Through a lineage tracing approach, we demonstrate that exogenously derived 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 dedifferentiation. 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.

Cellular Senescence is a Double-Edged Sword in Regulating Aged Immune Responses to Influenza

“…Recently, p16-expressing fibroblasts were found to be a critical population for maintaining barrier integrity and tissue remodeling in the lungs (36). Senescent cells have also been shown to play a key role in limb regeneration in amphibian models (37). Deletion of these cells may compromise the barrier function of tissues and result in aberrant immune cell trafficking or leaking of certain cytokines or chemokines into the circulation.…”

Nurturing longevity through natural compounds: Where do we stand, and where do we go?

“…Efficient clearance of senescent cells has been evaluated in centenarians in response to stressors, thereby promoting tissue remodeling and regeneration. This axis of senescence-clearance-regeneration is considered essential for maintaining tissue integrity and prevention of damaged cells accumulation (Chikenji et al, 2019;Jeon et al, 2017;Walters et al, 2023). In this context, B-cell lymphoma-extra large (Bcl-Xl), an important protein involved in apoptosis control in centenarians, is further believed to play a crucial role in attenuating the senescence response.…”

Tail and Spinal Cord Regeneration in Urodelean Amphibians

“…As the author suggested, these differences are explained by modifications of the molecular program that regulates the death/degeneration of muscle fibers [126]. In addition, Walters et al [128] reported the activity exhibited by senescent cells during limb regeneration in the newt. An assumption is made that the factors emitted by senescent cells activate the FGF-ERK signaling axis, thereby causing myotubules to enter the S-phase of cell cycle with production of mononuclear muscle progenitors [128].…”

“…In addition, Walters et al [128] reported the activity exhibited by senescent cells during limb regeneration in the newt. An assumption is made that the factors emitted by senescent cells activate the FGF-ERK signaling axis, thereby causing myotubules to enter the S-phase of cell cycle with production of mononuclear muscle progenitors [128]. Thus, the issue of the source of muscle tissue regeneration in the case of appendage regeneration in salamanders is still not fully addressed [129].…”