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Reversing the epigenetic state of oligodendrocyte precursors cells in multiple sclerosis

Periodic Reporting for period 2 - EPIScOPE (Reversing the epigenetic state of oligodendrocyte precursors cells in multiple sclerosis)

Reporting period: 2018-03-01 to 2019-08-31

"2.5 million people around the world live with multiple sclerosis (MS). In MS, disturbed immunologic function leads to destruction of myelin, causing a slower flow of information between nerve cells. Nerve cells in the brain communicate with each other by transmitting information in the form of electrical impulses. A cell type in the brain called oligodendrocytes optimizes this process by produce myelin, a substance that insulates nerve cells and allows electrical impulses to be transmitted at a higher speed.

In relapse-remitting MS, oligodendrocyte progenitor cells, which are present in the adult brain, can complete their maturation process and produce myelin at the site of lesions. However, in progressive MS, oligodendrocyte progenitor cells are not able to mature, for reason yet to be determined. As such, a possible therapy for progressive MS could consist to override this blockage of oligodendrocyte progenitor cell maturation, so they would be able to produce myelin and restore the ability of nerve cells to transmit information at high speed.

All cells in the body carry the same genetic material, known as the genome. Nevertheless, different cells interpret their genome differently and express different repertoires of molecules, which will determine how the cell functions. We can imagine a cell as an orchestra that can make different interpretations of the notes of a musical piece (genome) depending on the maestros and which instruments are available in the orchestra. The maestros and instruments that cells use to read and interpret the genome include molecules such as transcription factors, non-coding RNAs and enzymes.

Oligodendrocyte progenitor cells in progressive MS interpret the genome differently from myelin producing oligodendrocyte progenitor cells in healthy individuals, due to their different repertoire of ""maestros/instruments"" they have at their disposal. The goal of EPIScOPE is to identify molecules in oligodendrocytes that affect myelination and to develop pharmacological agents that can regulate the activity of the identified molecules and contribute to remyelination in MS.
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In EPIScOPE, we have used a new emerging technology, called single-cell transcriptomics, that allows to identify in one single cell which molecules the cell has available. We have used this technology to establish a comprehensive library how oligodendrocytes are different during normal development and in MS.

In one study published in 2018 in Developmental Cell, we found that oligodendrocytes forget their origins throughout their life, unlike other nerve cells. Oligodendrocytes originate in different locations in the brain and spinal cord. When their ancestor cells are first generated during the early stages of life, they have different properties depending on the region they come from. We found that the ancestor cells of oligodendrocytes are different depending on which region of the brain they come from. These differences are later lost, and the cells become very similar independently of where they end up.

In another study published in Nature Medicine in 2018, we found that a subset of oligodendrocytes and their progenitor cells in a mouse model of MS have much in common with the immune cells. Among other properties, they can take part in the clearing away of the myelin that is damaged by the disease. Oligodendrocyte progenitor cells can also communicate with the immune cells and make them change their behaviour. We observed that some genes that have been identified as those that cause a susceptibility to MS are active (expressed) in oligodendrocytes and their progenitors. Thus, our experiments suggest that these cells have a significant role to play either in the onset of the disease or in the disease process.

We also mapped oligodendrocytes in human samples from post-mortem brains of MS patients, in collaboration with Prof. Anna Williams and Charles ffrench-Constant at University of Edinburgh, and the pharmaceutical company Roche in Basel. We found changes in different oligodendrocyte subpopulations in MS, suggesting a more complex role of these cells in the pathology of the disease, but also in regeneration of new cells. For instance, we found that oligodendrocyte precursor cells, which are thought to have a crucial role in relapsing-remitting MS to restore myelin, are depleted in the progressive disease. This paper was recently published in Nature, in January 2019.

We will now continue to investigate and modulate the activity of the identified molecules in oligodendrocytes and determine if we can alter the character of the cells and their capacity to mature and produce myelin, or modulate the immune system.
In EPIScOPE, my group has been combining state-of-the-art technologies, including single-cell RNA sequencing, epigenomics, quantitative proteomics, and fluorescence-activated cell sorting (FACS) in transgenic animals and rodent models of disease, with standard biochemical, molecular and cell biology techniques, such as chromatin and RNA immunoprecipitation, among others. As mentioned above, this approach has allowed us to uncover novel aspects of oligodendrocyte and MS biology. In particular, the discovery of immune oligodendroglia is paradigm-shifting to the field, and might open new avenues of research in the area. In the last half of the grant period, we aim to further explore how these different disease-specific oligodendrocyte states arise, and which molecular players are important. We aim to manipulate the identified molecules, to pave the way to novel therapeutical strategies for MS.
Oligodendrocyte precursor cells clearing myelin debris and interacting with immune cells in MS