Chronically denervated distal nerve stump inhibits peripheral nerve regeneration

Schwann cells (SCs) and peripheral nerve regeneration: SCs are the principal glial cells of the peripheral nervous system (PNS). In a healthy nerve, myelinating SCs wrap around larger caliber motor and sensory axons to form the myelin sheath, whereas non-myelinating SCs envelop and support multiple small diameter sensory axons to form Remak bundles. Moreover, they form a basal lamina which surround each SC-axon unit (Hall, 2005). When a peripheral nerve injury occurs, extensive changes in the differentiation state of both the damaged neurons and the SC distal to the injury site take place. As a response to nerve injury, SC change their function by changing their gene expression: they down-regulate myelin-associated genes (such as myelin protein zero, myelin basic protein, myelin-associated glycoprotein, peripheral myelin protein 22, the Krox-20 transcription factor and periaxin) and up-regulate genes important to support repair and regeneration (such as L1 cell adhesion molecule, neural cell adhesion molecule, p75 neurotrophin receptor p75, and glial fibrillary acidic protein) (Jessen and Mirsky, 2016). They dedifferentiate into immature SC and proliferate, forming columnar structures known as Bands of Büngner that guide axons back to their target organs. These processes, together with the up-regulation of neurotrophic factors and receptors (including glial cell line-derived neurotrophic factor, artemin, brain-derived neurotrophic factor, neurotrophin-3, nerve growth factor, vascular endothelial growth factor, erythropoietin, pleiotrophin, p75 and N-cadherin (Jessen and Mirsky, 2016), the phagocytic role of SC to remove axonal and myelin debris and the recruitment of macrophages to help in clearing, create a supportive environment for nerve regeneration (Arthur-Farraj et al., 2012). Moreover, in a recent study, Ronchi et al. (2016) investigated the expression of different neuregulin 1 (NRG1) isoforms (that is one of the most important factors regulating SC activity) in distal rat median nerve samples under regenerating condition and they demonstrated that their expression is specific for distinct and consecutive phases following nerve injury and regeneration. In particular, they showed that soluble isoforms of NRG1 are strongly up-regulated early (few days) after nerve injury, suggesting an active role of this molecules in the response to nerve damage (Ronchi et al., 2016). Finally, when a successful axonal regeneration has occurred, SC regain their contact with axons and redifferentiate again into myelinating (or non-myelinating) cells. Due to this surprising degree of plasticity displayed by SC after nerve injury, these cells are considered key factors in promoting nerve regeneration.