Myelination potential and injury susceptibility of grey versus white matter human oligodendrocytes

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.