Exosomes derived from Schwann cells (SCs) promote non-cell-autonomous regeneration of neurons upon nerve damage; they contain proteins and non-coding RNAs that regulate axonal regeneration. In response to injury, SCs reprogram into repair SCs (rSCs) through the transcriptional activation of c-Jun and Sox2. This change in SC phenotype is associated with their regenerative capacity, but it is not known whether this also affects their exosome content and activity. Now, Felipe Court and colleagues (López-Leal et al., 2020) have found that reprogramming of SCs leads to altered exosome cargo and growth-promoting capabilities. Treating cultured SCs with forskolin induces the shift to rSCs, and exosomes derived from these rSCs show a higher regenerative capacity than those of differentiated SCs (dSCs) in dorsal root ganglia explants. Downregulation of c-Jun or Sox2 in these rSCs decreases the ability of their exosomes to stimulate neurite growth, whereas exosomes secreted by HEK cells overexpressing c-Jun or Sox2 are able to promote neurite extension. Finally, rSC-derived exosomes have increased levels of miRNA-21 compared to those from dSCs, which is crucial for their regenerative capacity as it targets phosphatase and tensin homolog (PTEN) and activates the PI3-kinase signalling pathway in the regenerating neuron. Hence, this study uncovers one of the functional shifts that enhances the pro-regenerative capabilities of rSCs through the modification of their exosomal cargo.
