Cui Qiao-Ling, Mohammadnia Abdulshakour, Yaqubi Moein, Weng Chao, Dorion Marie-France, Pernin Florian, Hall Jeffery A, Dudley Roy, Stratton Jo Anne, Kennedy Timothy E, Srour Myriam, Antel Jack P
Neuroimmunology Unit, Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada.
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
Brain. 2025 Mar 6;148(3):921-932. doi: 10.1093/brain/awae311.
Increasing evidence indicates heterogeneity in functional and molecular properties of oligodendrocyte lineage cells both during development and in pathological conditions. In multiple sclerosis, remyelination of grey matter lesions exceeds that in white matter. Here, we used cells derived from grey matter versus white matter regions of surgically resected human brain tissue samples to compare the capacities of human A2B5-positive progenitor cells and mature oligodendrocytes to ensheath synthetic nanofibres, and we related differences to the molecular profiles of these cells. For both cell types, the percentage of ensheathing cells was greater for grey matter versus white matter cells. For both grey matter and white matter samples, the percentage of cells ensheathing nanofibres was greater for A2B5-positive cells versus mature oligodendrocytes. Grey matter A2B5-positive cells were more susceptible than white matter A2B5-positive cells to injury induced by metabolic insults. Bulk RNA sequencing indicated that separation by cell type (A2B5-positive versus mature oligodendrocytes) is more significant than by region, but segregation for each cell type by region is apparent. Molecular features of grey matter- versus white matter-derived A2B5-positive and mature oligodendrocytes were lower expression of mature oligodendrocyte genes and increased expression of early oligodendrocyte lineage genes. Genes and pathways with increased expression in grey matter-derived cells with relevance for myelination included those related to responses to the external environment, cell-cell communication, cell migration and cell adhesion. Immune- and cell death-related genes were upregulated in grey matter-derived cells. We observed a significant number of upregulated genes shared between the stress/injury and myelination processes, providing a basis for these features. In contrast to oligodendrocyte lineage cells, no functional or molecular heterogeneity was detected in microglia maintained in vitro, probably reflecting the plasticity of these cells ex vivo. The combined functional and molecular data indicate that grey matter human oligodendrocytes have increased intrinsic capacity to myelinate but also increased injury susceptibility, in part reflecting their being at a stage earlier in the oligodendrocyte lineage.
越来越多的证据表明，少突胶质细胞谱系细胞在发育过程中和病理状态下的功能和分子特性存在异质性。在多发性硬化症中，灰质病变的髓鞘再生超过白质。在这里，我们使用从手术切除的人脑组织样本的灰质和白质区域获得的细胞，比较人类A2B5阳性祖细胞和成熟少突胶质细胞包裹合成纳米纤维的能力，并将这些差异与这些细胞的分子谱相关联。对于这两种细胞类型，灰质细胞包裹纳米纤维的细胞百分比高于白质细胞。对于灰质和白质样本，A2B5阳性细胞包裹纳米纤维的细胞百分比高于成熟少突胶质细胞。灰质A2B5阳性细胞比白质A2B5阳性细胞更容易受到代谢损伤诱导的损伤。批量RNA测序表明，按细胞类型（A2B5阳性与成熟少突胶质细胞）分离比按区域分离更显著，但每种细胞类型按区域的分离是明显的。灰质和白质来源的A2B5阳性和成熟少突胶质细胞的分子特征是成熟少突胶质细胞基因表达降低，早期少突胶质细胞谱系基因表达增加。在灰质来源的与髓鞘形成相关的细胞中表达增加的基因和途径包括那些与对外界环境的反应、细胞间通讯、细胞迁移和细胞粘附相关的基因。免疫和细胞死亡相关基因在灰质来源的细胞中上调。我们观察到应激/损伤和髓鞘形成过程之间有大量上调的基因共享，为这些特征提供了基础。与少突胶质细胞谱系细胞相反，在体外培养的小胶质细胞中未检测到功能或分子异质性，这可能反映了这些细胞在体外的可塑性。功能和分子数据相结合表明，灰质人类少突胶质细胞具有增加的内在髓鞘形成能力，但也增加了损伤易感性，部分反映了它们处于少突胶质细胞谱系中较早的阶段。
