Exploring the spatio-temporal dynamics of CXCR4 in peripheral nerve regeneration

Peripheral neurons, including motor neurons, possess the ability to regenerate following nerve injury. This process relies on an orchestrated response driven by intrinsic neuronal properties and a permissive environment, with Schwann cells (SCs) playing a central role. The developmental signalling axis CXCR4/CXCL12α is a core component of the regenerative process. The receptor CXCR4 becomes rapidly up-regulated following nerve damage and its stimulation favours repair. We hypothesize that early injury signals initiating the repair program - among them neuronal hydrogen peroxide (H2O2) - may be the triggers of CXCR4 up-regulation. Notably, following nerve injury CXCR4 increases at both protein and transcript levels, but with different localizations: the former in the axons, the latter mainly in myelinating SCs (mSCs). This suggests that SCs, activated by alarm signals generated at the injury site, may provide Cxcr4 transcripts to the regenerating axon, likely exploiting extracellular vesicles (EVs) as delivery mechanism. Here, I tested the hypothesis that H2O2 is responsible for Cxcr4 up-regulation using in vitro primary cultures of SCs and in vivo the sciatic nerve model, and that these cells deliver the transcript to the injured nerve. I could confirm that H2O2 is one of the triggers of SCs’ injury response, as it stimulates Cxcr4 transcription in mSCs. Moreover, I detected Cxcr4 mRNAs in SCs-derived EVs, further confirming the pro-regenerative function of these cells.