Altered oligodendrocyte heterogeneity in Multiple sclerosis.. Altered oligodendrocyte heterogeneity in Multiple sclerosis.

Oligodendrocyte (OL) pathology is increasingly implicated in neurodegenerative diseases, as they are involved in metabolic support of axons and functional cross-talk with other brain cells. Rodent OLs are heterogeneous, with developmental and biological differences, but the extent of heterogeneity in the normal human brain and its contribution to any changes of disease remains unknown. Here we performed single nuclei RNA-sequencing (snRNA-seq) from white matter (WM) areas of post mortem human brain both in control (Ctr) and multiple sclerosis (MS) patients. We identified several sub-clusters of oligodendroglia in the Ctr human WM, some similar to those in mouse, and defined new markers for these. Strikingly, some of these sub-clusters were under-represented in MS tissue, while others were more prevalent than in controls. There was a lack of OL precursor cells (OPCs) and OLs in an intermediate stage of differentiation in MS lesions and in normal appearing white matter (NAWM), suggesting either depletion by the disease or by a regenerative response. The differences in mature OL sub-clusters indicate different functional states of OLs in MS tissue and, as this is similar in NAWM to lesions, that MS is a more diffuse brain disease than the focal demyelinating lesions suggest. We were also able to identify new markers of different MS lesion subtypes. Our findings of an altered heterogeneity of oligodendroglia in MS may have an important contribution to our understanding of disease progression and may alter therapeutic approaches to MS. Overall design: We isolated single nuclei from white matter post-mortem tissue from 5 non-neurological control samples (Ctrl) and post-mortem tissue from 4 progressive Multiple sclerosis (MS) patients. We got a total of 20 samples, which in the MS samples included different non-lesioned (normal appearing white matter) and lesioned (active lesions, chronic active lesions, chronic inactive lesions and remyelinating lesions) based on pathology, to address the cellular and functional differences between the two groups. Note from submitter: Since the data is from human patients, we will submit the raw data to dbGap, that allows human sequence data