The repair Schwann cell and its function in regenerating nerves

Abstract

Nerve injury triggers the conversion of myelin and non‐myelin (Remak) Schwann cells to a cell phenotype specialized to promote repair. Distal to damage, these repair Schwann cells provide the necessary signals and spatial cues for the survival of injured neurons, axonal regeneration and target reinnervation. The conversion to repair Schwann cells involves de‐differentiation together with alternative differentiation, or activation, a combination that is typical of cell type conversions often referred to as (direct or lineage) reprogramming. Thus, injury‐induced Schwann cell reprogramming involves down‐regulation of myelin genes combined with activation of a set of repair‐supportive features, including up‐regulation of trophic factors, elevation of cytokines as part of the innate immune response, myelin clearance by activation of myelin autophagy in Schwann cells and macrophage recruitment, and the formation of regeneration tracks, Bungner's bands, for directing axons to their targets. This repair programme is controlled transcriptionally by mechanisms involving the transcription factor c‐Jun, which is rapidly up‐regulated in Schwann cells after injury. In the absence of c‐Jun, damage results in the formation of a dysfunctional repair cell, neuronal death and failure of functional recovery. c‐Jun, although not required for Schwann cell development, is therefore central to the reprogramming of myelin and non‐myelin (Remak) Schwann cells to repair cells after injury. In future, the signalling that specifies this cell requires further analysis so that pharmacological tools that boost and maintain the repair Schwann cell phenotype can be developed.

Chromatin-remodeling enzymes in control of Schwann cell development, maintenance and plasticity

“…Regenerative properties of the PNS after lesion are to a large extent due to the plasticity of SCs that first dedifferentiate and convert into repair cells in response to injury to foster and guide axonal regrowth, and second redifferentiate to remyelinate regenerated axons [3,5,7,10]. These different key steps of the regeneration process involve the dynamic regulation of many genes and thus the timed action of several transcription factors, which are known to promote either SC de-differentiation or redifferentiation after lesion.…”

“…By contrast, myelin is detrimental for axonal regrowth after lesion, because it contains growth inhibitory proteins [5]. However, SCs react quickly to an axonal lesion by dedifferentiating, digesting their own myelin -a process called myelinophagy [6] -and converting into repair cells [7,8] that foster axonal regrowth and guide axons back to their former target [9,10]. SCs then remyelinate regenerated axons (Figure 2).…”

Autophagy in Peripheral Neuropathy

“…The myelin protein zero (MPZ), myelin basic protein (MBP), and myelin associated glycoprotein (MAG) are downregulated. Neurotrophic factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), neurotrophin-3 (NT3), and vascular endothelial growth factor (VEGF) are upregulated [6,20]. Growth associated protein (GAP-43) is upregulated in injured peripheral nerve, and in the growth cone [21,22].…”

“…Growth associated protein (GAP-43) is upregulated in injured peripheral nerve, and in the growth cone [21,22]. SCs also activate innate immunity by releasing cytokines such as tumor necrosis factor α (TNF α) and interleukin-1α and β which promote recruitment of macrophages and stimulate axonal regeneration [6].…”

“…SCs are a type of glial cells in the PNS. They support axons, maintain homeostasis, produce neurotrophic factors, provide myelin sheath to isolate the axons, and have an immune role during nerve injury [4,6]. SC membrane is normally wrapped around the axon and isolates the axons, which leads to faster propagation of the nerve signal (action potential).…”