Animals such as amphibians have an incredible capacity for regeneration with some being able to regrow their tail or appendages. Although some mammalian tissues like the skin and bones can repair following injury, there are only a few examples of true multilineage regeneration, including the distal portion of the digit tip. In both amphibians and mammals, however, to achieve successful repair or regeneration, it is now appreciated that intact nerve innervation is a necessity. Here, we review the current state of literature and discuss recent advances that identify axon-derived signals, Schwann cells, and nerve-derived mesenchymal cells as direct and indirect supporters of adult tissue homeostasis and repair. We posit that understanding how nerves positively influence repair and regeneration could lead to targeted regenerative medicine strategies to enhance tissue repair in humans.
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