Cellular senescence promotes progenitor cell expansion during axolotl limb regeneration

• Published in: Developmental cell Vol. 58; no. 22; pp. 2416 - 2427.e7
• Main Authors: Yu, Qinghao, Walters, Hannah E., Pasquini, Giovanni, Pal Singh, Sumeet, Lachnit, Martina, Oliveira, Catarina R., León-Periñán, Daniel, Petzold, Andreas, Kesavan, Preethi, Subiran Adrados, Cristina, Garteizgogeascoa, Ines, Knapp, Dunja, Wagner, Anne, Bernardos, Andrea, Alfonso, María, Nadar, Gayathri, Graf, Alwin M., Troyanovskiy, Konstantin E., Dahl, Andreas, Busskamp, Volker, Martínez-Máñez, Ramón, Yun, Maximina H.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 20.11.2023
• Subjects: blastema; cellular senescence; ribosomal RNA processing; salamander; Wnt; ribosomal RNA processing; cellular senescence; salamander; blastema; Wnt
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2023.09.009

Axolotl limb regeneration is accompanied by the transient induction of cellular senescence within the blastema, the structure that nucleates regeneration. The precise role of this blastemal senescent cell (bSC) population, however, remains unknown. Here, through a combination of gain- and loss-of-function assays, we elucidate the functions and molecular features of cellular senescence in vivo. We demonstrate that cellular senescence plays a positive role during axolotl regeneration by creating a pro-proliferative niche that supports progenitor cell expansion and blastema outgrowth. Senescent cells impact their microenvironment via Wnt pathway modulation. Further, we identify a link between Wnt signaling and senescence induction and propose that bSC-derived Wnt signals facilitate the proliferation of neighboring cells in part by preventing their induction into senescence. This work defines the roles of cellular senescence in the regeneration of complex structures. [Display omitted] •Senescent cells comprise a pro-regenerative niche during axolotl limb regrowth•Senescent cells promote progenitor proliferation via the modulation of WNT signaling•WNT signaling prevents blastema progenitors from undergoing senescence•The regenerative senescence program is distinct from DNA-damage-induced senescence Yu et al. address the features, heterogeneity, and functions of senescent cells that arise during axolotl limb regeneration, showing that senescent cells form a niche that sustains limb progenitor proliferation in a short-range manner via WNT signaling. This work defines the roles of cellular senescence in the regeneration of complex structures.