Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis

Abstract

Introductory Multiple Sclerosis (MS) is characterised by an immune system attack targeting myelin, which is produced by oligodendrocytes (OLs). We performed single-cell transcriptomic analysis of OL lineage cells from the spinal cord of mice induced with experimental autoimmune encephalomyelitis (EAE), which mimics several aspects of MS. We found unique OLs and OL precursor cells (OPCs) in EAE and uncovered several genes specifically alternatively spliced in these cells. Surprisingly, EAE-specific OL-lineage populations expressed genes involved in antigen processing and presentation via major histocompatibility complex class I and II (MHC-I and -II), and in immunoprotection, suggesting alternative functions of these cells in a disease context. Importantly, we found that disease-specific oligodendroglia are also present in human MS brains and that a substantial number of genes known to be susceptibility genes for MS, so far mainly associated with immune cells, are expressed in the OL lineage cells. Finally, we demonstrate that OPCs can phagocytose and that MHC-II expressing OPCs can activate memory and effector CD4+ T cells. Our results suggest that OLs and OPCs are not passive targets but instead active immunomodulators in MS. The disease-specific OL lineage cells, for which we identify several biomarkers, may represent novel direct targets for immunomodulatory therapeutic approaches in MS.

The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury

“…OPCs contribute to the glial scar and through their expression of the NG2 proteoglycan may regulate axonal growth and dieback (Filous et al, ; Hackett et al, ). They may also regulate inflammatory responses after SCI and are capable of antigen presentation and cytokine production (Falcao et al, ; Kang et al, ; Moyon et al, ). These potential novel functions of OPCs in tissue remodeling after injury could be critical mediators of functional recovery and may provide new therapeutic avenues to promote recovery.…”

“…In vivo gene profiling confirms that oligodendrocyte‐lineage cells express the major histocompatibility complex Genes I and II in response to cytokines like IFNγ (Falcao et al, ; Kirby et al, ). Additionally, OPCs phagocytose antigens in reaction to IFNγ stimulation, and subsequently present these antigens to CD4+ T‐helper cells to support their survival and proliferation (Falcao et al, ). OPCs also present antigens to activate CD8+ cytotoxic T‐cells (Kirby et al, ).…”

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

“…Another important cell category is the microglia-macrophage-like cells important for scavenging cellular debris and protein aggregates, but when activated they also become central players in brain inflammation. With the available data from the normal unperturbed situation as a benchmark, gene expression changes related to diseases now start to be elucidated, for example, in Alzheimer's disease (AD) [11] and multiple sclerosis [12], where single-nuclei RNA sequencing technology has been used to capture transcriptomes at single-cell resolution. Thus, more than 500 molecularly distinct classes of neurons and glial cells have been identified in the mouse brain [1,2], and information about the cellular composition of specific brain regions is increasing rapidly [2][3][4][5][6][7][8].…”

“…Most data thus far are derived from the mouse, but progress is made in understanding cell type diversity also in the human brain [10]. With the available data from the normal unperturbed situation as a benchmark, gene expression changes related to diseases now start to be elucidated, for example, in Alzheimer's disease (AD) [11] and multiple sclerosis [12], where single-nuclei RNA sequencing technology has been used to capture transcriptomes at single-cell resolution. It is expected that several additional diseases, in particular those that can be faithfully recapitulated in mouse models, will be transcriptomically analyzed in a not too distant future.…”

Heterogeneous fate choice of genetically modulated adult neural stem cells in gray and white matter of the central nervous system

“…Heterogeneity among oligodendroglial progenitor cells (OPCs) has previously been related to their gray (GM) or white matter (WM) localization in the central nervous system (CNS; (Lentferink, Jongsma, Werkman, & Baron, ; Vigano, Möbius, Götz, & Dimou, )). Based on single cell sequencing data, this information has recently been expanded describing regional differences among oligodendroglial cells (Marques et al, ) as well toward disease‐specific lineages upon demyelination (Falcao et al, ; Jäkel et al, ). Moreover, new reports point to an additional contribution to myelin repair in the adult CNS from partially lesioned oligodendrocytes (Duncan et al, ; Yeung et al, ).…”