Schwann Cells: Development and Role in Nerve Repair

Abstract

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).T he myelin and nonmyelin (Remak) Schwann cells of adult nerves originate from the neural crest in well-defined developmental steps ( Fig. 1). This review focuses on embryonic development (for additional information on myelination, see Salzer 2015). We also discuss how the ability to change between differentiation states, a characteristic attribute of developing cells, is retained by mature Schwann cells, and explain how the ability of Schwann cells to change phenotype in response to injury allows the peripheral nervous system (PNS) to regenerate after damage. TWO TYPES OF EMBRYONIC NERVESAdult nerves are stable structures in which the nerve fibers are protected structurally by a collagen-rich, vascularized extracellular matrix (the endoneurium) linked to the basal lamina surrounding each axon -Schwann cell unit. The endoneurial environment is further protected by a surrounding multilayered cellular tube (the perineurium) that shields the nerve fibers from unwanted cells and molecules (Fig. 2).A more dynamic and radically different structure, reminiscent of axon -glial organization in the central nervous system (CNS), is seen in early embryonic nerves (embryo day E14/15 in rat hind limb and E12/13 in mouse). These nerves consist of tightly packed axons and flattened, glial cell processes without significant extracellular space, matrix, or basal lamina. The glial cell bodies lie among the axons inside the nerve or at the nerve surface. These cells represent the first stage of the Schwann cell lineage, Schwann cell precursors (Figs. 3 and 4).

Inflammaging impairs peripheral nerve maintenance and regeneration

“…Wallerian degeneration is a prerequisite for efficient regeneration of injured nerves and involves several different cell types, including macrophages and other immune cells (Chen et al, 2007; Jessen et al, 2015). …”

“…Expression of MCP1 is reported for denervated Schwann cells, to recruit macrophages to the injury site (Deshmane et al, 2009; Tofaris et al, 2002), then assist Schwann cells in cellular debris clearing, and stimulation of axonal regrowth (Dubovy, Jancalek, & Kubek, 2013; Jessen et al, 2015). But persistent MCP1 expression produces a chronic inflammatory state, hindering nerve regeneration (Kato et al, 2001).…”

“…Hallmarks of Wallerian degeneration are as follows: (a) detachment of resident Schwann cells from associated axons, (b) transition of these Schwann cells into a “repair Schwann cell” phenotype, (c) breakdown of the blood–nerve barrier, and (d) influx of macrophages into the tissue that, (e) in concert with “repair Schwann cells,” phagocytize axonal and myelin‐derived debris (Chen, Yu, & Strickland, 2007; Jessen, Mirsky, & Lloyd, 2015). During the regeneration phase, macrophages support “repair Schwann cells” in mediating axonal regrowth to re‐innervate the target tissue (Cattin et al, 2015; Mietto, Mostacada, & Martinez, 2015; Mokarram, Merchant, Mukhatyar, Patel, & Bellamkonda, 2012).…”

Myelination and mTOR

“…Myelin synthesis continues into adulthood in a temporally and spatially controlled manner (Baumann & Pham‐Dinh, 2001; Jessen, Mirsky, & Lloyd, 2015; Snaidero & Simons, 2017). As most cellular products, also myelin undergoes turnover, although the extent and rate are not completely clear.…”

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

“…The last step of maturation is the myelination process where SCs build a thick myelin sheath rich in lipids around axons (Figure 1). Meanwhile, small caliber axons remain in bundles associated with non-myelinating SCs and persist as Remak bundles in adult nerves [3,4]. Myelin provides axonal insulation and fast conduction of electric signals along axons; its formation and maintenance are thus critical for neuronal functions.…”