Oligodendrocyte progenitor cell recruitment and remyelination in multiple sclerosis: the more, the merrier?

Abstract

Promoting remyelination in order to prevent/reduce neurodegeneration in patients with multiple sclerosis (MS) is a major therapeutic goal. The longstanding view that the block of oligodendrocyte progenitor cell (OPC) differentiation in MS lesions is the leading cause of remyelination failure has inspired the scientific community to focus primarily on OPC differentiation-promoting compounds as pro-remyelinating agents. Yet, these strategies have been challenged by findings that active MS lesions contain surviving oligodendrocytes that may contribute to remyelination, while many chronic lesions contain low numbers of oligodendroglial cells. In addition, clinical trials using differentiation-stimulating drugs have shown limited efficacy. Thus, a strategic shift in the design of potential remyelination-promoting therapies may be required to achieve significant clinical benefits, which calls for a careful reconsideration of the mechanisms underlying remyelination failure in MS. Here, we argue that both the rate and the efficacy of OPC recruitment are fundamental determinants of remyelination, and that stimulating this process in MS may be crucial to achieve myelin regeneration. We first review different types of MS lesions in early and chronic MS, with a particular focus on OPCs and surviving oligodendrocytes. Based on the neuropathological findings and results obtained using models of demyelination, we make the case that OPC differentiation block in chronic MS is likely the consequence of defective OPC recruitment during earlier phases of the disease because: 1. if the recruitment is too slow, OPCs reach the axons after what we define as “remyelination-permissive window”, and thus remain undifferentiated; and 2. if the recruitment is inefficient, OPC density in the lesions remains below the threshold required for differentiation. Importantly, we highlight that OPC proliferation in MS lesions is scarce, which strongly suggests that repeated episodes of demyelination/remyelination (OPC differentiation) will deplete the lesional OPC pool unless perilesional OPCs are recruited. We also point out that surviving mature oligodendrocytes in a subtype of early MS lesions may actually prevent the recruitment of OPCs. Because it has been suggested that OPC-mediated remyelination may be more efficient than that by surviving oligodendrocytes, we suggest that stimulating OPC recruitment during active disease should benefit remyelination in multiple types of lesions, including those with spared oligodendrocytes. Finally, we review molecular determinants of OPC recruitment and suggest a potential therapeutically-relevant strategy to increase this process in patients with MS.

Endothelin-1–Endothelin receptor B complex contributes to oligodendrocyte differentiation and myelin deficits during preterm white matter injury

“…In line with this speculation, OPC transplantation in animals has been shown to effectively increase recovery from preterm WMI and spinal cord injury (Porambo et al, 2015). Nevertheless, the differentiation of transplanted OPCs is severely inhibited by the adverse microenvironment caused by brain injury, albeit they can migrate to the lesions (Tepavcevic and Lubetzki, 2022). Given that improving the capacity of transplanted OPCs to differentiate is a key step for the treatment of preterm WMI, uncovering the molecular mechanisms controlling OPC differentiation during preterm WMI is essential to OPC transplantation therapy.…”

What Are the Roles of Oligodendrocyte Precursor Cells in Normal and Pathologic Conditions?

“…Oligodendrocyte precursor cells have a complex role in multiple sclerosis (MS) (reviewed in Reference 25). Adult OPCs seem to have only a limited role in myelin regeneration after demyelinating lesions in humans, 27,122 whereas surviving oligodendrocytes upregulate their expression of myelination-related genes and are able to regenerate new myelin sheaths.…”

“…27,123 The progressive oligodendrocyte depletion over the course of MS may reflect partly their defective proliferation and recruitment to the lesion. 25,[124][125][126][127] Studies in pluripotential stem cell-derived oligodendroglia from patients with MS show that OPCs conserve their ability to interact with axons and generate myelin, indicating that failure of remyelination does not reflect an intrinsic defect of OPCs. 128 Some observations indicate that OPCs make new myelin more efficiently than preexisting oligodendrocytes.…”

Astrocytic phagocytosis of myelin debris and reactive characteristics in vivo and in vitro

“…The imbalance between demyelination and remyelination affects the occurrence and development of demyelinating diseases. At present, the treatment of remyelination should involve the following four aspects: (i) Clearing myelin debris; (ii) improving the microenvironment of myelin regeneration; (iii) inducing the generation of OL precursor cells (OPCs); and (iv) accelerating OPC differentiation (Tepavčević & Lubetzki, 2022). It has been noted that myelin phagocytosis and further degradation increase the density of OPCs in areas of demyelination and the generation of mature OLs, thus enhancing remyelination and axonal integrity (Cignarella et al., 2020).…”