Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation

Author:

Walters Hannah E.1,Troyanovskiy Konstantin E.12,Graf Alwin M.1,Yun Maximina H.134ORCID

Affiliation:

1. Technische Universität Dresden, CRTD/Center for Regenerative Therapies Dresden Dresden Germany

2. Freie Universität Berlin Berlin Germany

3. Max Planck Institute for Molecular Cell Biology and Genetics Dresden Germany

4. Cluster of Excellence Physics of Life Technische Universität Dresden Dresden Germany

Abstract

AbstractSalamanders 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.

Funder

Deutsche Forschungsgemeinschaft

Publisher

Wiley

Subject

Cell Biology,Aging

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