Guest post: Multiple Sclerosis from a researcher’s perspective


Multiple Sclerosis (MS) is an incurable neurological disorder that is characterized by the loss of specialized functional cells in our brain. Oligodendrocytes are one of these specialized cell types that play an important role in MS. They produce a fatty substance called myelin, which is produced in large sheaths that are tightly wrapped around our nerve cells. Myelin is essential for providing nutrients to them, but also to speed up our brain activity. In MS, myelin and oligodendrocytes are lost for unknown reasons, resulting in the distinct lesions that are visible in MRI scans. Human brains are quite flexible, they can initially cope with this loss and eventually repair the damage – a process that we call remyelination – but in the long run, the remyelination capacity of oligodendrocytes decreases and the lesions remain. As the nerve cells are losing both their protection and their fuel, they degenerate in late stages of MS, leading to the various devastating symptoms of people living with the disease.

Although we know what happens during the disease, the reasons for this are less well understood and a lot of current research – including ours – is addressing this question. We are using a novel technology called single-nuclei RNA-sequencing that allows us to analyse thousands of individual brain cells at a much deeper resolution than ever before. With this, we compared oligodendrocytes of post-mortem brains of people that were living with MS and non-neurological controls to better understand the oligodendrocyte biology of the human brain and to detect the pathological changes of the disease. In our recent publication (Jaekel et al. 2019), we found that our brain contains distinct subtypes of oligodendrocytes that can be distinguished by the expression of different markers. We think that these heterogeneous oligodendrocytes do have different functions. Our current and future research is focusing on this. In MS, the composition of these subtypes is shifted, with some subtypes being over- and some underrepresented. We don’t know yet whether this skew in oligodendrocyte heterogeneity is the result of some oligodendrocytes being more prone to death or some oligodendrocytes being predominantly replaced.

Available medication is targeting the immunological component in early stages of the disease, which proves to be efficient for a limited time. Unfortunately, there is no available therapy tackling brain repair and nerve cell degeneration at the later stages of the disease. Current research strategies for new therapeutic approaches are therefore aiming at improving the new generation of oligodendrocytes and thus active remyelination. By gaining a better knowledge about oligodendrocytes in our brain, our work is a very important step towards understanding the cellular changes that are happening in this disease and thus paves the way for new strategies to treating MS.

By Sarah Jaekel

Sarah Jaekel (nee Schneider) is a postdoctoral research fellow at the Centre for Regenerative Medicine (University of Edinburgh, Scotland). Her main research interest focuses on human oligodendrocyte heterogeneity in healthy brains as well as in neurodegenerative diseases such as Multiple Sclerosis and Alzheimers.

After finishing her Master’s degree in Molecular Biotechnology in 2011, Sarah became interested in neuroscience – particularly in oligodendroglia. During her PhD, which she obtained from the Graduate School of Systemic Neuroscience at the Ludwig-Maximilians-University in Munich (Germany) in 2016, she elaborated the role of proliferating oligodendrocyte progenitor cells in health and disease in rodents. In order to extend her research to humans, Sarah moved to Edinburgh to start her current position. With her work on human oligodendrocytes, she was awarded the European Marie-Skłodowska Curie fellowship in 2018. Sarah is

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  • Barts team dont like T reg cells

    But apparently they important for remyelination

    Efficient myelin regeneration in the central nervous system (CNS) requires the migration, proliferation and differentiation of oligodendrocyte progenitor cells (OPC) into myelinating oligodendrocytes. In demyelinating diseases such as multiple sclerosis (MS), this regenerative process can fail, and therapies targeting myelin repair are currently completely lacking in the clinic. The immune system is emerging as a key regenerative player in many tissues, such as muscle and heart. We recently reported that regulatory T cells (Treg) are required for efficient CNS remyelination. Furthermore, Treg secrete CCN3, a matricellular protein from the CCN family, implicated in regeneration of other tissues. Treg-derived CCN3 promoted oligodendrocyte differentiation and myelination. In contrast, previous studies showed that CCN2 inhibited myelination. These studies highlight the need for further scrutiny of the roles that CCN proteins play in myelin development and regeneration. Collectively, these findings open up exciting avenues of research to uncover the regenerative potential of the adaptive immune system.

    • No Barts Team arent really bothered about T regs as we dont work with them. When we have it has not always gone to plan. However we are not lemmings and remember the same experiments with different explanations and we see square pegs being put into round holes. Maybe we can get another guest post on them from Northern Ireland.

      Did CD4 depletion make MS worse, did daclizumab inhibit recovery? I will put the experiment down as a student experiment, do it ourself and let’s see what we get.

  • Also a proinflamatory cytokine is important

    Pro-inflammatory IL-1β enhances oligodendrocyte progenitor cell proliferation and differentiation and promotes myelin protein production


    Oligodendrocytes (OL) are the myelinating cells of the central nervous system (CNS). In order for myelination to occur, oligodendrocyte progenitor cells (OPCs) undergo proliferation followed by differentiation into mature OL that form new myelin around axons. In MS the myelin sheath is damaged (demyelination), however, myelin regeneration (remyelination) can occur in early stages of the disease but often fails with disease progression due to impaired OL differentiation. Intriguingly, remyelination is boosted in areas of inflammation, while the absence of inflammatory signals might reduce successful myelin regeneration. IL-1β was suggested to promote CNS repair in an animal model of MS, but the function of this proinflammatory cytokine in OPC biology and myelination remains incompletely understood.

    Inflammasomes are intracellular protein complexes that initiate an immune response upon danger sensing. Activated inflammasomes consist of a danger sensor (e.g. NLRP3), the adaptor protein ASC and caspase-1. Their major function is to generate the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18), which recruit immune cells and initiate an inflammatory response.

    This project aims to determine the function of inflammasome product IL-1β on oligodendroglial lineage cells including OPC proliferation, survival, differentiation and myelin protein production.

    Mixed glial and pure glial cultures were used to investigate the impact of IL-1 on OPC biology and myelin protein production in a) the context of other CNS cells, e.g. astrocytes, microglia and neurons, and b) in isolation. Upon exposure to IL-1 glial cells were fluorescently stained and survival, proliferation, differentiation and myelin protein production was quantitatively analysed.

    IL-1β exposure resulted in enhanced OPC differentiation and in increased myelin basic protein (MBP) production, one of the major proteins of CNS myelin. This effect was mediated through IL-1R1 signaling in glial cells.

    Conversely, IL-1β also increased OPC proliferation in our cultures. As OPC can either differentiate or proliferate but not both simultaneously this suggests that OPC of distinct differentiation stages in our cultures respond differentially to IL-1β.

    We here show that proinflammatory IL-1β impacts on OPC development and that OPC differentially respond to this cytokine, which was found in lesions and CSF of MS. Further analysis aims to uncover the underlying mechanisms, which might lead to the development of novel IL-1β targeted MS therapies.

By BartsMSBlog



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