Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation

• Published in: Aging cell Vol. 22; no. 6; pp. e13826 - n/a
• Main Authors: Walters, Hannah E., Troyanovskiy, Konstantin E., Graf, Alwin M., Yun, Maximina H.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-06-2023; John Wiley and Sons Inc
• Subjects: Amputation; Animals; Cell cycle; Cell Dedifferentiation; Cellular Senescence; dedifferentiation; ERK; FGF; Genotype & phenotype; Kinases; Life span; Limbs; Mammals; Muscle Fibers, Skeletal - metabolism; Myotubes; Physiology; Proteins; Regeneration; reprogramming; salamander; Salamanders; Salamandridae - physiology; Senescence; Stem cells; Transcriptomics; WNT; reprogramming; cellular senescence; FGF; regeneration; dedifferentiation; salamander; WNT; ERK
• ISSN: 1474-9718; 1474-9726; 1474-9726
• DOI: 10.1111/acel.13826

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.
Senescent cells enhance salamander limb regeneration through the promotion of muscle dedifferentiation. Senescent cell‐derived secreted factors activate the FGF‐ERK signalling axis leading to reversal of muscle identity and cell cycle re‐entry in newt myotubes, critical steps for the generation of muscle regenerative progenitors.