The multicellular complexity of peripheral nerve regeneration

•Regeneration of the PNS is a complex, highly coordinated, multicellular process.•Macrophages have multiple roles to condition the environment for axonal regrowth.•Schwann cells guide and nurture regrowing axons back to their targets.•Polarised blood vessels direct Schwann cell migration across the region of injury.

Peripheral nerves show a remarkable ability to regenerate following a transection injury. Downstream of the cut, the axons degenerate and so to regenerate the nerve, the severed axons need to regrow back to their targets and regain function. This requires the axons to navigate through two different environments. (1) The bridge of new tissue that forms between the two nerve stumps and (2) the distal stump of the nerve that remains associated with the target tissues. This involves distinct, complex multicellular responses that guide and sustain axonal regrowth. These processes have important implications for our understanding of the regeneration of an adult tissue and have parallels to aspects of tumour formation and spread.