**5. Schwann cell plasticity**

PNS has a very good regenerative capacity, and this is largely due to Schwann cells that develop a high plasticity and can contribute very quickly to the regeneration of peripheral nerves after injury whether it is a trauma or a pathological condition. In these cases, SCs have the ability to transform into an immature-like form, which drives subsequent regeneration of the nerve. These processes of dedifferentiation into non-myelinating cells and redifferentiation after injury are characteristic of these glial cells in PNS, and in the last decade a significant progress has been made in the study of the molecular mechanisms and signaling pathways that regulate this plasticity (reviewed in [42]). More of this, the myelinating and non-myelinating SCs remain bipotential cells all the time, as demonstrated by grafting or nerve cross anastomosis experiments [43–45]. Many experimental studies on transgenic animals have shown that after nerve cut or crush, both types of SCs reprogram into proliferative progenitor-like repair SCs [46, 47]. This phenomenon involves downregulation of pro-myelinating genes, such as early growth response 2 (Egr-2 or Krox-20), POU domain class 3 transcription factor 1 (Pou3f1 or Oct-6), and myelin protein zero (MPZ)/myelin basic protein (MBP). There is also an upregulation of markers of dedifferentiated (immature) SCs like low affinity neurotrophin receptor (p75NTR), c-Jun, or glial fibrillary acidic protein (GFAP) [6].

After Wallerian degeneration following nerve injury, a downregulation of promyelinating genes occurs, and the myelin clearing phenomenon begins after myelin sheath disorganization, through a mechanism of autophagy or myelinophagy [48]. Macrophages also participate in this process, phagocytosing myelin and axonal debris. The recruitment of macrophages is also done by SCs [49–51].

One of the major problems of human SCs is that as their regenerative capacity decreases in time, they can no longer sustain axonal growth, and their numbers decrease greatly (reviewed in [52]).

Regarding the plasticity of Schwann cells, although not covered by this chapter, we just want to mention here that SC precursors can generate many and different

cell types during embryogenesis, besides myelinating and non-myelinating SCs, such as endoneurial fibroblasts, melanocytes, and neurons [52].
