Multiple Sclerose Centrum
Noord Nederland

INVESTIGATORS – Inge Zuhorn and Wia Baron

PROJECT –

Supported by the bloed-hersenbarriere-in-ms/" target="_blank" rel="noopener">Dutch MS Research Foundation
Project 22-1158

INVESTIGATORS – Jody de Jonge and Wia Baron

PROJECT –

Supported by the laesies-het-myeline-herstel/" target="_blank" rel="noopener">Dutch MS Research Foundation and Monique Blom-de Wagt/Fund Girn
Project 21-1118

INVESTIGATORS – Rianne Gorter, Jolien Fledderus, Naomi Dijksman and Wia Baron

PROJECT –

Supported by the Dutch MS Research Foundation
Project 20-1105

INVESTIGATORS –  Naomi Dijksman, Sander van Kasteren, Wia Baron

PROJECT – MS is a disease of the central nervous system for which the cause is still unknown. In MS, myelin, the insulating layer surrounding nerve fibres, degenerates (demyelination). This results in a decrease in nerve impulse conduction, and ultimately in degeneration of nerve cells. Oligodendrocytes are the cells that form myelin and disappear together with myelin in people with MS.

A factors that increase the chances to develop MS is an infection with Epstein-Barr virus (EBV). EBV can also cause kissing disease (mononucleosis). A specific type of immune cells, the so-called B cells, are involved in both MS and EBV infection. After EBV infection, a large portion of B cells become inactive. Clusters of these dormant B-cells have been detected in the brain tissue of people with MS. Additionally, these dormant EBV-infected B-cells appear to produce clumps of protein (aggregates). These aggregates are made of a protein that is present in myelin, which is not degraded in EBV-infected B cells. The EBV-infected B-cells release the aggregates into the tissue environment, which may be harmful to surrounding cells. In this project, we will investigate whether and how these protein aggregates are involved in degeneration of oligodendrocytes and demyelination. We anticipated that this research will bring us a step closer to the cause of MS.

Supported by MoveS via the Dutch MS Research Foundation
Project 19-1067

INVESTIGATORS –  Jody de Jong, Wendy Oost, Marion Wijering, Susanne Kooistra, Wia Baron and Bart Eggen.

PROJECT – Multiple sclerosis (MS) is characterized by the presence of lesions (affected areas) in the central nervous system. These lesions indicate the disappearance of myelin (demyelination) and failure of the regeneration of myelin (remyelination) and lead to neurological deficits. During the disease course different types of lesions are formed, all with their own characteristics such as active lesions (areas with abundant inflammatory cells and demyelination, but with remyelinated areas), mixed active/inactive lesions (demyelinated areas with inflammatory cells around the edge) and inactive lesions (demyelinated areas without inflammatory cells and hardly  signs of remyelination). There is still no answer to the question: Why does the regeneration process of myelin often fail in MS?

This challenging project is divided in 3 subprojects that are closely related and in which different techniques are applied to find an answer to this important question.

1. Examine the cell composition and gene expression changes between and within different lesion types.

In this project an innovative technique is used, called spatial transcriptomics. This technique enables the possibility to detect the activity of specific genes on their actual location in the tissue and to compare gene-activity between and within different lesion types. The contribution of (local) alterations in gene-activity in a certain cell type to failure of remyelination will be functionally studied.

2. Characterize the environment of the cells in different lesion types.

In this project, the focus is not on the cells but on the supporting tissue laying around the cells, the so-called extracellular matrix. Using proteomics, we examine which proteins are present in the extracellular matrix of the different types of lesions. Using functional assays, we will  focus  on the proteins that are most dominantly present and may  play a role in the remyelination failure. The ultimate goal is to find means to manipulate proteins that inhibit the remyelination process, and thus overcome remyelination failure.

3. Reveal the surface characteristics of cells in different lesion types.

In this project, we aim to reveal if the remyelination failure can be caused by a miscommunication between the cells and their environment using cell surface proteomics. In addition, we make large scale electron microscopic images to literally zoom in and make a detailed characterization of unlesioned tissue and the different lesion types. This nanotomy technique makes it possible to compare subtle changes in appearance and composition of the cells and study changes in the interaction and space between the cells.

The three different PhD projects are closely related and have the mutual goal to better understand which proteins inhibit successful remyelination of different MS lesion types. The disturbed processes can ultimately be simulated in so-called brain-organoids, 3D mini-brains made from the cells of persons with MS. This can serve as a model to develop and validate new treatments to improve the regeneration of myelin.

Supported by the myeline-dichterbij/" target="_blank" rel="noopener">Dutch MS Research Foundation

Project 18-733c

INVESTIGATORS – Rianne Gorter, Jenny Dallinga-de Jonge, Sandra Amor, Harrie Kampinga and Wia Baron

PROJECT – In the brain and spinal cord of people with multiple sclerosis (MS), the myelin layer surrounding the fibers of nerve cells is damaged, leading to disease symptoms. In relapsing-remitting MS, cells called ‘oligodendrocytes’ repair the myelin layer, causing MS symptoms to disappear. Unfortunately, in most people these repair mechanisms eventually fail: the myelin will not be regenerated, nerve cells die and people develop ‘progressive MS’ with irreversible disability. When myelin is damaged, oligodendrocyte progenitor cells are recruited to the injured area. Next, these immature oligodendrocytes need to become mature oligodendrocytes and regenerate the myelin. We previously found that MS lesions contain clumps of fibronectin, a protein which is not present in healthy brain. These fibronectin clumps hamper the maturation of oligodendrocytes. Immature oligodendrocytes cannot repair myelin and thus MS symptoms will not disappear. This project will investigate, in a culture dish and in animal models, means to remove the fibronectin clumps to improve myelin repair and ultimately delay progressive MS.

Supported by a MD/PhD fellowship

INVESTIGATORS – Pauline van Schaik, Inge Zuhorn and Wia Baron

PROJECT – In multiple sclerosis (MS) the fatty substance that surrounds nerve endings in the brain and spinal cord (called myelin) degenerates, which leads to a plentitude of physical and cognitive symptoms. Regeneration of myelin (remyelination) is important for the recovery of symptoms. Unfortunately, the current available drugs used for treating MS do not influence myelin regeneration. In this project, we investigate a novel therapeutic compound that may be beneficial for inducing remyelination in an MS-specific lesion environment. Our previous findings have shown that this compound positively affects the brain cells responsible for producing myelin. When given to these cells in an MS-like setting, they start producing myelin. However, we are still far from administering this compound to people with MS, as it cannot easily travel to the brain when taken in its current form. Therefore, we will develop a molecular carrier that protects and encapsulates this novel therapeutic drug, while simultaneously directing it to the brain. Furthermore, we will test the efficacy of this carrier on human cells  derived from people with MS. This is made possible through a relatively new technology, that allows us to grow any type of cell from urine-derived cells. Hopefully this proof-of-concept study will bring us one step closer to an effective treatment for progressive MS.

Supported by the Dutch MS Research Foundation
Project 16-944

INVESTIGATORS – Mirjam Koster, Susanne Kooistra, Bart Eggen and Wia Baron

PROJECT – MS is a complicated disease in which the pathology varies considerably per patient. Especially the progression of the disease, the localisations of the lesions in the central nervous system (CNS) and the involved cell types are prominent factors of variation. Both cell types characteristic to the CNS – including neurons, astrocytes, oligodendrocytes and microglia – and infiltrating immune cells contribute to the variable MS pathology. Recent research has demonstrated that there is cellular heterogeneity in MS lesions, meaning that the presence of different cell populations within the cell types varies between lesions. At the moment, not much is known about the contribution of this cellular heterogeneity to the pathology and the progression of MS. This research project focusses on understanding the role of cellular heterogeneity and cell-cell interactions in the development and progression of MS lesions.

Supported by a GSMS PhD fellowship

INVESTIGATORS – Tiago Medeiros Furquim Mendonça, Amalia Dolga, Erik Boddeke, Susanne Kooistra, and Bart Eggen

PROJECT – In addition to adaptive immune cells, innate immune cells can also develop immunological memory. The tissue-resident innate immune cells of the central nervous system, microglia, can acquire immunological memory, which is underpinned by long-lasting epigenetic and metabolic reprogramming. Microglia sense their microenvironment with highly motile processes, and respond to tissue perturbations and become activated. Microglia can acquire diverse activation states, dependent on the type, duration and frequency of the stimulus, and epigenetics is key for this range in microglia phenotypes. Inflammatory stimuli or tissue damage can induce innate immune memory in microglia and alter their response to a subsequent challenge.

MS is an inflammatory neurodegenerative disease characterized by demyelinated lesions with oligodendrocyte loss, and progressive reduction in axons in the CNS.  Microglia, the CNS-resident macrophages, are also widely implicated in MS. Their role in MS is complex, as microglia are reported to have both tissue-supportive and detrimental functions, depending on the stage of MS. How innate immune memory in microglia is involved in MS pathology is the main focus of this project.

INVESTIGATORS – Anneke Miedema, Nieske Brouwer, Bart Eggen and Susanne Kooistra

PROJECT – Multiple sclerosis (MS) is a common disease of the central nervous system (CNS), characterized by chronic inflammation, demyelination and neuronal damage. Different lesion types develop within the CNSof MSpatients in both grey and white matter, resulting in a wide variety of symptoms including impaired mobility. This project aims to get a better understanding of lesion development and lesion progression in MS. My focus will be on the role of microglia in this process. Microglia are the innate immune cells of the CNS and they also play important roles in brain homeostasis. We will study this by using novel transcriptomic methods to identify microglia/lesion specific gene expression profiles in human post-mortem brain tissue from MS patients. Understanding how lesions are formed and how they progress might lead to new insights for drug targets. Next, we will use MS-like animal models (EAE and cuprizone) models to modulate microglia specific candidate genes, which will be identified by the transcriptomic analysis.

Supported by the Dutch MS Research Foundation

INVESTIGATORS – Anneke Miedema en Susanne Kooistra

PROJECT – Glial cells fulfill multiple essential functions in the central nervous system (CNS). Especially a particular type of glial cell that represents the innate immune system in the CNS, microglia, are implicated in the origins and progression of MS.  As a result they provide a potential therapeutic target. However, the exact contribution of microglia to disease progression is unclear. In MS patients a wide variety of microglia phenotypes are observed depending on their exact location in respect to lesions as well as the type of lesion. In order to determine if and how microglia are true therapeutic targets in MS, we aim to identify these differences between individual cells on a molecular level.

Supported by the Dutch MS Research Foundation (personal fellowship)

INVESTIGATORS – Chairi Misrielal, Fulvio Reggiori, Susanne Kooistra, and Bart Eggen

PROJECT – Autophagy is an intracellular degradation system essential for cellular homeostasis. This process acts as a housekeeper by eliminating defective proteins and organelles, preventing accumulation of protein aggregates, and is increasingly considered to be a key regulator of (neuro)inflammation. Microglia, the macrophages of the central nervous system (CNS), are involved in the maintenance of CNS homeostasis and immune activation of microglia plays an important role in many neurodegenerative diseases, including multiple sclerosis (MS). Preliminary data in a mouse model for MS pointed to changes in microglia autophagy. This project aims to understand how (disturbed) microglial autophagy is involved in MS. We hypothesize that autophagy is essential for efficient clearance of cell debris in MS. As such, autophagy in microglia may contribute to the disease process as impairment in autophagy may hinder debris clearance, and as a consequence negatively interfere with remyelination.

Supported by a GSMS PhD fellowship

INVESTIGATORS – Malte Borggrewe, Bart Eggen, Randolph Noelle, Jon Laman

PROJECT – Although the treatment of MS is strongly improved, there are no drugs that halt the disease. Hence, there is a need to develop new approaches. In collaboration with prof. Randolph Noelle (Dartmouth College, New Hampshire, USA) we work on a new target, a molecule named VISTA. In the immune system, VISTA limits the function of T cells, inflammatory cells essential to development and acivity of MS. By engaging the VISTA molecule with novel drugs we aim to limit T-cell activity and hence MS disease activity.

The project aims to provide the foundation for a future drug to activate VISTA. The reverse approach, the blockade of VISTA to amplify immunity against cancer cells is already being pursued in clinical trials. This supports the promise of our approach. Application in MS requires substantial research and development.

Supported by the Dutch MS Research Foundation