Achucarro Basque Center for Neuroscience, University of the Basque Country, Leioa, Spain.
INSERM UMR1127 Sorbonne Université, Paris Brain Institute (ICM), Paris, France.
Brain. 2022 Dec 19;145(12):4178-4192. doi: 10.1093/brain/awac307.
Promoting remyelination 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 (i) if the recruitment is too slow, OPCs reach the axons after what we define as 'remyelination-permissive window', and thus remain undifferentiated; and (ii) 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.
促进髓鞘再生以预防/减少多发性硬化症 (MS) 患者的神经退行性变是一个主要的治疗目标。长期以来，人们认为 MS 病变中少突胶质前体细胞 (OPC) 分化受阻是髓鞘再生失败的主要原因，这激发了科学界主要关注促进 OPC 分化的化合物作为促髓鞘再生药物。然而，这些策略受到了以下发现的挑战：活跃的 MS 病变中含有可能有助于髓鞘再生的存活少突胶质细胞，而许多慢性病变中少突胶质细胞数量较少。此外，使用分化刺激药物的临床试验显示疗效有限。因此，可能需要对潜在的髓鞘再生促进治疗的设计进行战略转变，以实现显著的临床获益，这需要仔细重新考虑 MS 中髓鞘再生失败的机制。在这里，我们认为 OPC 募集的速度和效率都是髓鞘再生的基本决定因素，在 MS 中刺激这一过程对于实现髓鞘再生可能至关重要。我们首先回顾了早期和慢性 MS 中的不同类型的 MS 病变，特别关注 OPC 和存活的少突胶质细胞。基于神经病理学发现和脱髓鞘模型的结果，我们提出，慢性 MS 中的 OPC 分化受阻可能是疾病早期阶段 OPC 募集缺陷的结果，因为：(i) 如果募集太慢，OPC 会在我们定义的“髓鞘再生允许窗口”后到达轴突，因此保持未分化状态；(ii) 如果募集效率低下，病变中的 OPC 密度仍低于分化所需的阈值。重要的是，我们强调 MS 病变中的 OPC 增殖很少，这强烈表明，除非募集到旁皮质 OPC，否则反复的脱髓鞘/髓鞘再生（OPC 分化）将耗尽病变中的 OPC 池。我们还指出，早期 MS 病变中的一种亚型中存活的成熟少突胶质细胞实际上可能会阻止 OPC 的募集。由于有人提出 OPC 介导的髓鞘再生可能比存活的少突胶质细胞更有效，我们建议在活动期疾病中刺激 OPC 募集应该有益于多种类型病变中的髓鞘再生，包括那些有少突胶质细胞保留的病变。最后，我们回顾了 OPC 募集的分子决定因素，并提出了一种潜在的治疗相关策略，以增加 MS 患者的这一过程。
