The regeneration of mammalian peripheral nerves after injury requires glial cells called Schwann cells (SCs), which dedifferentiate to a progenitor-like state to direct the regeneration process. However, whether an additional stem cell population contributes to injury-induced SCs, and how plastic SC fate is during the regeneration process, have remained controversial issues. Now, Alison Lloyd and colleagues provide a comprehensive characterisation of the regenerating murine sciatic nerve. After confirming that SCs represent the majority of resident cells in the nerve, the authors show that sciatic SCs show very little turnover in the adult; indeed, not one instance of myelinating SC (mSC) cell division was observed over 70 days. Despite this quiescence, the vast majority of SCs proliferate extensively within days of an injury and migrate to the cut site. After their injury-induced dedifferentiation, mSCs remyelinate normally, and the authors find no evidence in support of an additional stem cell or progenitor population contributing to SCs. SC fate plasticity during regeneration is limited: mSCs can contribute to non-myelinated mSCs and vice versa. Increased mSC fate plasticity is observed in tumour models, suggesting its induction by genetic and microenvironmental factors. The remarkable transition from quiescence to regeneration in peripheral nerves is thus orchestrated not by a resident stem cell population but mature cells with proliferative capacity and limited fate plasticity.
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