RNA-Seq reveals new clues to the origin and progression of multiple sclerosis

Mapping of a certain group of cells, known as oligodendrocytes, in the central nervous system of a mouse model of multiple sclerosis (MS), shows that they might have a significant role in the development of the disease. The discovery can lead to new therapies targeted at other areas than just the immune system. The results are published in Nature Medicine by researchers at Karolinska Institutet in Sweden.

2.5 million people around the world live with MS, with approximately 18,000 people in Sweden, and about 1,000 new cases annually. MS develops when the immune system’s white blood cells attack the insulating fatty substance known as myelin that coats nerve fibres in the central nervous system. This interferes with the proper transmission of nerve electric signals and causes the symptoms of the disease. While it is unknown why the immune system attacks the myelin, a study by researchers at Karolinska Institutet shows that the cells that produce myelin, oligodendrocytes, might play an unexpected role. Oligodendrocytes are one of the most common types of cell in the brain and spinal cord.

“Our study provides a new perspective on how multiple sclerosis might emerge and evolve” says Gonçalo Castelo-Branco, associate professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet. “Current treatments mainly focus on inhibiting the immune system. But we can now show that the target cells of the immune system in the brain and spinal cord, oligodendrocytes, acquire new properties during disease and might have a higher impact on the disease than previously thought.”

The researchers have shown that a subset of oligodendrocytes and their progenitor cells have much in common with the immune cells, in a mouse model of MS. Among other properties, they can take part in the clearing away of the myelin that is damaged by the disease, in a way that resembles how immune cells operate. Oligodendrocyte progenitor cells can also communicate with the immune cells and make them change their behaviour.

“We also see that some genes that have been identified as those that cause a susceptibility to MS are active (expressed) in oligodendrocytes and their progenitors,” says Ana Mendanha Falcão, joint first author of the study with David van Bruggen, both at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet.

“All in all, this suggests that these cells have a significant role to play either in the onset of the disease or in the disease process,” says David van Bruggen.

The study was conducted using the recently developed technique, single-cell RNA sequencing, which provides scientists with a snapshot of the genetic activity of single cells and therefore with a much more effective means of differentiating the properties of individual cells. This has made it possible for researchers to identify the various roles and functions of the different cells.

Single-cell RNA sequencing of OL lineage cells in response to EAE uncovers
new disease-specific populations and disease markers

rna-seq

a, Schematic overview of the methodology used to perform single-cell RNA-seq of the OL lineage cells. b, Clinical score of the diseased animals used in the study (n = 12 mice; data represented as mean ± s.e.m.; only animals that reached score 3 and one that reached score 2.5 were used in this study). c, t-Distributed stochastic neighbor embedding (t-SNE) plots of all cells sequenced showing the segregation of cells derived from CFA controls and EAE (n = 4 biologically independent mouse spinal cord samples per condition; total number of cells is 794 for controls and 971 for EAE). d, t-SNE plots of all cells sequenced representing different cell populations within OL lineage cells. MOL identities were defined according to marker genes identified in ref. 4 (n = 4 biologically independent mouse spinal cord samples per condition; total number of cells is 745 for controls and 707 for EAE). e,f, Violin plots depicting the expression of specific markers for OPCs (e) and for MOL clusters (f) (n = 4 biologically independent mouse spinal cord samples per condition; total number of cells is 116 for OPC controls and 132 for OPC EAE and 626 for MOL controls and 575 for MOL–EAE). Violin plots are centered around the median with interquartile ranges and shape represents cell distribution. g, t-SNE plots of disease-specific markers for OL lineage cells (n = 4 biologically independent mouse spinal cord samples per condition; total number of cells is 745 for controls and 707 for EAE). h, Schematic representation of the exon 6 inclusion in the Pdgfa gene in response to EAE. i, Violin plot representing the proportion of spliced isoform (PSI) in controls (MOL2 Ct-a depicted in green) and EAE (MOL1/2–EAE depicted in purple) of the alternative spliced exons in Pdgfa and Mbp genes. PSI = 0 means totally excluded and PSI = 1 totally included (n = 4 biologically independent mouse spinal cord samples per condition; total number of cells is 56 for MOL2 Ct-a and 49 for MOL1/2–EAE; Pdgfa ex6: P = 0.0003176 and Mbp ex2: P = 5.323 × 10−11 by two-sided Wilcoxon rank-sum test with continuity correction; violin plots are centered around the median with interquartile ranges and shape represents cell distribution. VLMCs, vascular and leptomeningeal cells; MiGl, microglia-like cells.

Although the study was largely conducted on mice, some of the results have also been observed in human samples.

“We will now continue with further studies to ascertain the part played by the oligodendrocytes and their progenitor cells in MS,” says Gonçalo Castelo-Branco. “Further knowledge can eventually lead the way to the development of new treatments for the disease.”

Source – Eurekalert

Mendanha Falcão A et al. (2018) Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis. Nature Medicine [Epub ahead of print]. [abstract]

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