*2.1.3.2 RSCs in nerve injury and regeneration*

Transection of a nerve fiber initiates Wallerian degeneration of the distal stump. As opposed to oligodendrocytes, SCs maintain the ability to dedifferentiate to an immature phenotype in response to nerve injury or disease, and they can actively promote the repair and functional recovery. The repair SCs express inflammatory mediators, such as interleukins and TNFα, as well as anti-inflammatory cytokines (IL-10, Epo, or TGFβ) and growth factors shown to promote Wallerian degeneration, macrophage attraction, and axonal regeneration upon nerve injury [34].

A number of molecules have been shown to play important roles in modulating SC behavior after nerve injury.

LDL receptor-related protein 1 (LRP1) is a significant factor involved in the development and maintenance of Schwann Cells, both myelinating and NMSCs [39]. LRP1 is one of the molecules upregulated after various types of peripheral nerve injury.

The study of Campana et al. proved that LPR1 upregulation was directly correlated with local production of TNFα and TNFα/LPR1 signaling is one of the survival mechanisms for SC migration and survival observed in in vitro studies [40].

Another signaling receptor that plays an important role in regulation of Schwann cell-axon interactions is fibroblast growth factor receptor (FGFR). Fibroblast growth factor 2 (FGF2) is one of the essential regulators of peripheral nerve regeneration after injury [41]. Three of its receptors, expressed by Schwann cells and dorsal root ganglia neurons, are FGFR1, FGFR2, and FGFR3 which are all upregulated after nerve injury [42].

One day after nerve transection, all SCs start to proliferate within the basal lamina. One week post-injury, RSCs double in length, and after 4 weeks they are three-fold longer and were called repair-supportive Schwann cells. About 50% of repair cells derive from RSCs. The loss of axonal contact determines cells to branch. They form branches lying parallel to the main cell axis, building cellular columns and Bungner bands distal to injury site and offering the support of regenerating sprouts. They will further differentiate to myelinating cells after regeneration [43].

## *2.1.3.3 RSCs and sensory nerve fiber pathology*

Most unmyelinated C-fibers ensheathed by Remak cells are nociceptors [39]. They transmit pain information to the brain. Thus, the dysfunction of RSC induces an altered transmission of the nociceptive stimuli, which leads to severe neuropathic pain.

The specific loss of GABBR1 in SCs results in an increased number of C-unmyelinated fibers, leading to a hypersensitivity to thermal and mechanical stimuli. There is also an alteration of the locomotor coordination, without any injury. It is not known whether these consequences are caused only by the modification of the unmyelinated axon number [19].

Other in vivo studies showed that after injury, in LRP1 knockout animals, the resulting hypomyelination and impaired RSCs ensheathment lead to motor dysfunction and mechanical allodynia [39] without any traumatic injury. These pathological changes can cause notable painful symptoms such as mechanical allodynia [39]. In a model with partial nerve injury, the LRP-negative mice have a higher degree of RSC apoptosis, an accelerated degeneration, and further more severe pain in the LRP than the nonmutant mice [39]. These findings suggest the involvement

of RSC in the pathophysiology of neuropathic pain and the importance of LRP1 in the physiology of RSC and open the possibility of using RSC as a new therapeutic target in the treatment of neuropathic pain.

In an experimental study in vivo on FGFR1 and FGFR2 single and FGFR1/ FGFR2 double conditional knockout mice, Furusho et al. showed that lack of FGFR1 and FGFR2 signaling in NMSCs resulted in sensory axonal neuropathy in unmyelinated C-fibers and the impairment of thermal pain sensitivity [42]. Another study by Chen et al. performed on transgenic mice that postnatally express a dominant-negative ErbB receptor in NMSCs but not in the myelinating ones led to a progressive peripheral neuropathy with loss of unmyelinated axons and heat/ cold pain [44]. Altogether, such data suggest the important role of RSCs in in the modulation of pain sensitivity in peripheral sensory neuropathies.

Charcot-Marie-Tooth type 1A (CMTA1A) is a genetic disease of the peripheral nervous system in which demyelination and further aberrant remyelination occur in a repeated cycle, with an "onion bulb" appearance in microscopy. From the clinical point of view, CMT1A is characterized by weakness and muscle atrophy in the lower limbs and later on by sensory loss. Myelinating Schwann cells are classically known to be impaired in CMT1A, but it seems that there is also an impairment of the RSC [45]. A proliferation of RSC takes place as a response to the degeneration of the myelinated axons that appear to secrete mitogenic factors [45]. Unexpectedly, no degeneration occurs in the unmyelinated fibers [45]. These findings reveal that RSC are altered in CMT1A, but without any impact on the unmyelinated fibers, in comparison to the relation between myelinating SCs alteration and degenerated myelinated axons. Further studies need to elucidate the contribution of RSC to the pathogenesis of CMT1A.
