Schwann cell remyelination of the central nervous system: why does it happen and what are the benefits?

Abstract

Myelin sheaths, by supporting axonal integrity and allowing rapid saltatory impulse conduction, are of fundamental importance for neuronal function. In response to demyelinating injuries in the central nervous system (CNS), oligodendrocyte progenitor cells (OPCs) migrate to the lesion area, proliferate and differentiate into new oligodendrocytes that make new myelin sheaths. This process is termed remyelination. Under specific conditions, demyelinated axons in the CNS can also be remyelinated by Schwann cells (SCs), the myelinating cell of the peripheral nervous system. OPCs can be a major source of these CNS-resident SCs-a surprising finding given the distinct embryonic origins, and physiological compartmentalization of the peripheral and central nervous system. Although the mechanisms and cues governing OPC-to-SC differentiation remain largely undiscovered, it might nevertheless be an attractive target for promoting endogenous remyelination. This article will (i) review current knowledge on the origins of SCs in the CNS, with a particular focus on OPC to SC differentiation, (ii) discuss the necessary criteria for SC myelination in the CNS and (iii) highlight the potential of using SCs for myelin regeneration in the CNS.

Keywords: Schwann cells; astrocytes; central nervous system; myelin; oligodendrocyte progenitor cells; remyelination.

Figure 1.

Origins, migration and development of OPCs and Schwann cells. (a) In the rodent spinal cord, OPCs originate from the pMN domain in the ventral ventricular zone at approximately embryonic (E)12.5. This is followed by a second wave of progenitors in more dorsal regions, which then migrate throughout the spinal cord to myelinate white matter tracts [23]. Similarly, in the rodent telencephalon, the first wave of OPCs arise from ventral progenitor cells in the medial ganglionic eminence (MGE) at E12.5. Subsequently, a second wave of OPCs is generated several days later at about E15.5 by dorsal progenitor cells in the lateral ganglion eminence (LGE). After birth, cortex-derived progenitors give rise to the final wave of OPCs. (b) During the formation of the neural tube, neural crest cells arise from the tips of the neural folds. Neural cells initially form and accumulate at the dorsal surface of the tube, but soon migrate along with different pathways to differentiate into SC precursor cells, as well as progenitors of melanocytes, autonomic neurons, dorsal root sensory glia, chromaffin cells and other peripheral glia). SC precursor cells then transition into immature SCs upon neuregulin-1 (NRG1), fibroblast growth factor 2 (FGF2) and Notch signalling. While all immature SCs are thought to possess myelinating potential, only immature SCs in close association with large-diameter axons differentiate into myelinating SCs. By contrast, SCs that associate with smaller-diameter axons form bundles of non-myelinating Remak cells [32].

Figure 2.

Comparison of central and peripheral myelination. (a) Each oligodendrocyte in the CNS can extend cytoplasmic projections to form multiple, multi-layered myelin sheaths (pink) around different axons, whereas each SC in the PNS completely wraps around a single axon by laying down multiple layers of cell membrane, of which the innermost layers constitute the myelin sheath (purple). (b) There is typically one oligodendrocyte between two nodes of Ranvier, which is not covered by plasma membrane to allow action potentials to jump from node to node. (c) Compared to oligodendrocytes, SC myelinated axons possess thicker myelin sheaths. SCs also have an enlarged non-axonal domain due to the extra presence of the cytoplasm and nuclei, which is covered by the outermost layer, called the neurilemma.

Figure 3.

Schematic of Schwann cell remyelination. (a) Under homeostatic conditions, astrocytes, microglia, oligodendrocyte progenitor cells (OPCs) and myelinating oligodendrocytes are dispersed throughout the normal adult white matter. SCs are absent from the CNS. (b) Following demyelination oligodendrocytes and myelin are lost. In some instances, astrocytes can also be damaged. Subsequently, OPCs in in the vicinity of the lesion area are activated. (c) Activated OPCs are recruited into the lesion area by the release of pro-migratory and mitogenic factors, and the demyelinated region is repopulated by new OPCs. At the same time, a small subset of peripheral SCs transgress into the CNS due to breaks in the glia limitans. (d) Typically, the lesion centre (red) contains the fewest number of surviving astrocytes, and in the absence of astrocytic inhibition, OPCs differentiate into SCs, which form a 1 : 1 association with the axon, resulting in a single myelin sheath. Conversely, oligodendrocyte differentiation and remyelination predominates at the lesion border (yellow), where astrocytes are present. In a minority of cases, peripherally derived SCs migrate into the lesion site, where they make contact and myelinate exposed axons. Remyelination is mostly complete within 3 weeks after lesion.

Figure 4.

OPC cell fate decisions OPCs are multipotent and can differentiate into oligodendrocytes, astrocytes or SCs. OPC cell fate decisions are in part, dependent upon BMP signalling. When BMP signalling is blocked, such as when OPCs are in proximity to BMP suppressive astrocytes, OPCs predominantly differentiate into oligodendrocytes in vivo and in vitro. Conversely, when OPCs are exposed to high BMP signalling in culture, OPCs readily form astrocytes [76,77]; however, in vivo, few OPCs have been observed to produce astrocytes. Lineage tracing studies have demonstrated that following demyelinating injuries, adult OPCs can differentiate into SCs in astrocyte deficient areas [21]. Although BMP signalling is high within the lesion environment, BMP alone is not sufficient to produce OPC-derived SCs in vitro.