Macrophages are required for adult salamander limb regeneration

TLDR

Adult mammals fail to regenerate damaged tissues due to muted growth responses and fibrotic scarring, and while immune cells influence wound repair, the role of immune signaling in highly regenerative species like salamanders remains poorly understood. The study investigates the role of macrophages in axolotl limb regeneration by analyzing immune signaling. A comprehensive analysis of immune signaling during axolotl limb regeneration revealed a temporally defined requirement for macrophage infiltration. Dynamic cytokine/chemokine signaling is rapidly induced after amputation, but systemic macrophage depletion causes wound closure yet permanent regeneration failure with fibrosis and ECM dysregulation, which can be rescued by reamputation after macrophage replenishment, suggesting macrophage‑derived factors may promote regeneration in mammals.

Abstract

The failure to replace damaged body parts in adult mammals results from a muted growth response and fibrotic scarring. Although infiltrating immune cells play a major role in determining the variable outcome of mammalian wound repair, little is known about the modulation of immune cell signaling in efficiently regenerating species such as the salamander, which can regrow complete body structures as adults. Here we present a comprehensive analysis of immune signaling during limb regeneration in axolotl, an aquatic salamander, and reveal a temporally defined requirement for macrophage infiltration in the regenerative process. Although many features of mammalian cytokine/chemokine signaling are retained in the axolotl, they are more dynamically deployed, with simultaneous induction of inflammatory and anti-inflammatory markers within the first 24 h after limb amputation. Systemic macrophage depletion during this period resulted in wound closure but permanent failure of limb regeneration, associated with extensive fibrosis and disregulation of extracellular matrix component gene expression. Full limb regenerative capacity of failed stumps was restored by reamputation once endogenous macrophage populations had been replenished. Promotion of a regeneration-permissive environment by identification of macrophage-derived therapeutic molecules may therefore aid in the regeneration of damaged body parts in adult mammals.