Macrophages are a major immune cell type which roam the tissues engulfing invaders like bacteria and fungi. But they’re not just involved in gobbling up debris. They actively determine repair – for example they are important in human muscle repair.
When macrophages were removed from salamanders, it had a “devastating effect” on their ability to regrow limbs. The animals ended up with fibrosis (scarring) and a stump.
Godwin believes that chemicals released by the animals’ macrophages are essential for the regeneration process, and is conducting experiments now to investigate this.
“This really gives us somewhere to look for what might be secreted into the wound environment that allows for regeneration,” he says.
“The long-term plan is that we’ll know exactly what cocktail to add to a wound site to allow salamander-like regeneration under hospital conditions.”
The work has implications not just for entire limb regrowth, but for “smaller, less ambitious” goals such as scar-less healing. Although scars perform a useful function in stopping blood loss and preventing infection getting into a wound, they inhibit communication between cells and this prevents regeneration, says Simon. Down the track, using the salamander’s approach could maybe help with healing of burns, for instance, he suggests.
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.