**5.1 Schwann cell dedifferentiation**

After injury, SCs reacquire some capabilities from early development, like proliferation, production of growth factors, sorting, and myelination. A good review regarding the biology of Schwann cells is the one made by Kidd et al. [3].

SC behavior and fate is regulated by two sort of interactions: SCs-axon and SCsextracellular matrix/basal matrix. After 48 hours following axonal transection, SCs downregulate the production of myelin protein mRNAs [53] and upregulate trophic factors and cytokines [12–14] like NGF, BDNF, GDNF, and LIF, molecules necessary in axonal regeneration promoting into distal stump (reviewed in [54]). After axonal injury/transection, the axon is rapidly destroyed by a nonapoptotic autonomous mechanism [55]. SCs begin myelin degradation after axon injury, disassembling first the myelin internode starting with Schmidt-Lantermann incisure swelling [56, 57], following the dissolution of myelin in bubbles, ovoids, and balls. Macrophages finish the myelin degradation by phagocytosis [58]. It is not known exactly how much the SCs contribute to myelin degradation compared to macrophage participation, but it seems that it depends on the volume of the internode [59, 60]. During myelin degeneration, changes occur in the SC microtubule network, lysosome, and endosome positioning [61].

After nerve crush or transection, between the two stumps, over the lesion site, fibroblasts form a bridge, interacting with SCs [62]. The newly formed vasculature participates also in guiding the growing axons through this bridge to the distal end [63]. After a period of persistence of distal nerve stumps, distal axons disappear and dedifferentiated SCs proliferate, align, and begin emitting processes, forming the bands of Bungner (**Figure 1**), offering a physical and trophic support for the regrowth of axon [44, 60].

After the axonal regeneration, SCs differentiate once more in non-myelinating and myelinating cells to finish the functional recovery of the nerve. The regenerated myelin internodes (**Figure 5**) are shorter and thinner than the rest of the original ones in the proximal part of nerve [64].

### **5.2 Molecular mechanisms which control SC plasticity**

The molecular mechanisms that regulate SC plasticity are very complex and widely described in many studies in recent years (reviewed in [42]). Here we will briefly mention them.

### *5.2.1 Transcriptional factors*

One important transcriptional factor in SC reprogramming is **c-Jun**. Although it is downregulated or absent in the differentiation of SC, under pathological conditions c-Jun is particularly upregulated as described in various peripheral neuropathies [65–69], being a cross-antagonist of Krox-20 (a pro-myelinating transcription factor). c-Jun take part at the myelinophagy process [47] and participate also in the macrophage recruitment following nerve injury [70].

Another transcriptional regulator is **NICD**, an intracellular domain generated from neurogenic locus notch homolog protein (**Notch**) cleavage. SC proliferation and generation of immature SCs are controlled by Notch. But the same Notch is a negative regulator of myelination [71].

#### *Schwann Cell Plasticity in Peripheral Nerve Regeneration after Injury DOI: http://dx.doi.org/10.5772/intechopen.91805*

Nuclear factor kB (**NF-kB**), a transcription factor which regulates many physiological processes especially the inflammatory response, is very important for SC differentiation and myelination as *in vitro* studies showed [72–74].

In the recent years, a transcriptional repressor, **Zeb2**, has been investigated, and the researchers showed that it is implied in SC differentiation and myelination. The lack of Zeb2 in SCs results in a failure of SC maturation and in absence of myelin membranes [75].

Other factors which are overexpressed in SC dedifferentiation are **Sox-2**, paired box protein 3 (**Pax-3**), early growth response proteins 1 and 3 (**Egr-1** and **Egr-3**), and DNA-binding protein inhibitor 2 (**Id2**) [66, 76, 77]. Sox-2 is also necessary for the nerve bridge formation after nerve injury [62].

mTOR complex 1 (**mTORC1**) (reviewed in [78]) has a significant role on the transcriptome by controlling transcription factors [79–82]. It promotes anabolism, counting mRNA translation, and purine and pyrimidine synthesis [83, 84]. mTORC1 is necessary in radial sorting of axons by SCs, biosynthesis of lipids, and, on this basis, myelin growth [85, 86]. The mTORC1 activity is higher before myelination onset and decreases when myelination starts [87–89].
