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.

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The repair Schwann cell and its function in regenerating nerves

Myelination of axons in the nervous system of vertebrates enables fast, saltatory impulse propagation, one of the best-understood concepts in neurophysiology However, it took a long while to recognize the mechanistic complexity both of myelination by oligodendrocytes and Schwann cells and of their cellular interactions In this review, we highlight recent advances in our understanding of myelin biogenesis, its lifelong plasticity, and the reciprocal interactions of myelinating glia with the axons they ensheath In the central nervous system, myelination is also stimulated by axonal activity and astrocytes, whereas myelin clearance involves microglia/macrophages Once myelinated, the long-term integrity of axons depends on glial supply of metabolites and neurotrophic factors The relevance of this axoglial symbiosis is illustrated in normal brain aging and human myelin diseases, which can be studied in corresponding mouse models Thus, myelinating cells serve a key role in preserving the connectivity and 

Myelination of the nervous system: mechanisms and functions

Rodent models of nerve injury have increased our understanding of peripheral nerve regeneration, but clinical applications have been scarce, partly because such models do not adequately recapitulate the situation in humans. In human injuries, axons are often required to extend over much longer distances than in mice, and injury leaves distal nerve fibres and target tissues without axonal contact for extended amounts of time. Distal Schwann cells undergo atrophy owing to the lack of contact with proximal neurons, which results in reduced expression of neurotrophic growth factors, changes in the extracellular matrix and loss of Schwann cell basal lamina, all of which hamper axonal extension. Furthermore, atrophy and denervation-related changes in target tissues make good functional recovery difficult to achieve even when axons regenerate all the way to the target tissue. To improve functional outcomes in humans, strategies to increase the speed of axonal growth, maintain Schwann cells in a healthy, repair-capable state and keep target tissues receptive to reinnervation are needed. Use of rodent models of chronic denervation will facilitate our understanding of the molecular mechanisms of peripheral nerve regeneration and create the potential to test therapeutic advances.

Advances in peripheral nerve regeneration

Schwann cells develop from the neural crest in a well-defined sequence of events. This involves the formation of the Schwann cell precursor and immature Schwann cells, followed by the generation of the myelin and nonmyelin (Remak) cells of mature nerves. This review describes the signals that control the embryonic phase of this process and the organogenesis of peripheral nerves. We also discuss the phenotypic plasticity retained by mature Schwann cells, and explain why this unusual feature is central to the striking regenerative potential of the peripheral nervous system (PNS).

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Schwann Cells: Development and Role in Nerve Repair

Neuregulin-ERBB Signaling in the Nervous System and Neuropsychiatric Diseases

https://www.ucl.ac.uk/jessenmirsky/wp-content/uploads/2012/08/Neuron-paper.pdf

Annbily Banerjee

Papers

c-Jun Reprograms Schwann Cells of Injured Nerves to Generate a Repair Cell Essential for Regeneration