Regulation of tissue regeneration and repair by the peripheral nervous system

Amphibians display a remarkable capacity for tissue regeneration, with some able to regrow entire limbs. In mammals, while tissues such as skin, bones and skeletal muscles are capable of repair following injury, true multilineage regeneration is rare and restricted to the distal region of the digit tip. Although the mechanisms governing successful tissue repair and regeneration are still coming to light, it is now appreciated that innervation by local nerves is a necessary component of the regenerative microenvironment. In this Review, we examine the current state of the literature that identifies the role of axon-derived signals, Schwann cells and nerve-derived mesenchymal cells as direct and indirect supporters of tissue repair and regeneration. We will also discuss how these cells function under pathological conditions or situations of aberrant tissue repair. Altogether, these findings underscore the significance of elucidating the role of the peripheral nervous system in tissue homeostasis and repair, with potential implications for the development of targeted therapeutic interventions and regenerative medicine strategies.