The conceptual introduction of the “demyelinating Schwann cell” in peripheral demyelinating neuropathies

Abstract

Myelinating Schwann cells undergo irreversible demyelination in many demyelinating neuropathies that show complete demyelination of the internode. Dedifferentiation, reprogramming, and myelin clearance processes—which are specifically discussed in this article—appear to be shared by various demyelinating peripheral conditions, such as Wallerian degeneration, immune‐mediated, and toxic demyelinating diseases. We propose to introduce the concept of the “demyelinating Schwann cell (DSC)” as a novel cell phenotype, which has specific properties required for myelin sheath clearance. We anticipate that the introduction of the DSC concept will provide a significant advance in understanding the pathophysiological mechanisms of demyelinating peripheral neuropathies.

p75 and neural cell adhesion molecule 1 can identify pathologic Schwann cells in peripheral neuropathies

“…Recent studies have demonstrated that the phenotypic changes of Schwann cells (SCs), the peripheral glia, such as dedifferentiation, are implicated in the pathophysiology of demyelinating neuropathies . SC dedifferentiation indicates a phenotypic transition of mature SCs into an immature type and is typically found during Wallerian degeneration (WD) after axonal injury . Dedifferentiated SCs activate several self‐myelinolytic mechanisms, including autophagolysosomes, to contribute to myelin clearance during WD .…”

“…Dedifferentiated SCs activate several self‐myelinolytic mechanisms, including autophagolysosomes, to contribute to myelin clearance during WD . Interestingly, dedifferentiated SCs also appear to be actively involved in inflammatory demyelination as components of “demyelinating SCs (DSCs)” . However, abnormal differentiation of immature SCs results in supernumerary nonmyelinating or dysmyelinating SCs in CMT1a, thereby contributing to the development of demyelinating neuropathy .…”

Schwann cell demyelination is triggered by a transient mitochondrial calcium release through Voltage Dependent Anion Channel 1

“…This pulse of mitochondrial calcium through VDAC1 activates the known demyelination pathways ERK1/2, p38 and JNK leading to cJun phosphorylation in the nucleus, which characterizes the demyelination program in myelinating SC (35). However several other unclear cellular processes are also engaged and this will result in the collapse of the cell structure, the breakdown of the myelin (3,4) and the recruitment of macrophages to help to clear myelin debris (4). Once demyelination is completed, around 5 days after crush of sciatic nerve, then dedifferentiated SC will be able to remyelinate axons.…”

“…In crushed nerves treated with vehicle, the myelin sheath was fragmented in ovoids compared to non-injured nerves (Fig. 6G) due to the collapse of the Schmidt-Lantermann incisures, which represents the first morphological feature of demyelination (3,4). This fragmentation was quantified or by counting the number of ovoids or by counting the percentage of demyelinating fibers (Fig.…”

“…Indeed, in case of peripheral nerve injury, the distal part of the axons degenerate, SC terminate their myelin sheath and enter a dedifferentiation program called Wallerian demyelination (3). The myelin is then digested by the SC themselves or by macrophages that are recruited (4). When axons have grown back, a re-myelination process then starts to restore a quasi-perfect myelin sheath (5).…”