Multiple Sclerose Centrum
Noord Nederland

1. Develop novel and innovative therapeutic tools for remyelination therapy based on intervention with the local molecular and cellular environment.


Molecular environment

The research on developing innovative therapeutic tools for remyelination therapy based on the intervention with the molecular environment investigates the local signaling environment in relation to the outgrowth of oligodendrocytes. To this end, we aim at revealing environmental restrictions in MS lesions that underlie remyelination failure to identify novel therapeutic targets. Accordingly, we aim to device strategies that reverse signal malfunctioning so as to favor the development of therapeutic tools to promote endogenous remyelination and/or overcome remyelination failure in MS lesions, thereby halting disease progression.

 

Projects

Hidden virus as inducer of demyelination in MS?

Inverstigators – Naomi Dijksman, Sander van Kasteren, Wia Baron

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

The therapeutic role of galectin-4 in the regeneration of myelin in MS

INVESTIGATORS –  Charlotte de Jong, Jenny Dallinga-de Jonge and Wia Baron

PROJECT – Oligodendrocytes are responsible for the production of myelin, which wraps around nerve processes, the axon. Because of this insulating myelin layer, the nerve impulses are efficiently transmitted. In affected brain regions (‘lesions’) in MS, where myelin is degraded, oligodendrocytes lack the ability to regenerate myelin. During the development of the brain, the protein galectin-4 – which is produced by nerve cells – acts as a switch for the production of myelin. In the absence of galectin-4, oligodendrocytes produce myelin, while that production is switched off when galectin-4 binds to oligodendrocytes. This binding spot act as a switch: it is always ‘on’, but is switched off as soon as galactin-4 binds. In this way, the production of myelin is accurately controlled by oligodendrocytes. In this project, we aim to unravel whether galectin-4 also plays a role in the regeneration of myelin. We also aim to identify the identity of the galectin-4-sensitive switch on the oligodendrocyte. In this way, we expect to be able to operate the switch, which is supposedly ‘off’ at MS, ‘remotely control it’ and turn it ‘on’ again. Another therapeutic entry to stimulate new production of myelin in MS lesions is the elimination of galectin-4 from the affected areas.

Supported by the Dutch MS Research Foundation

Delivery of a novel therapeutic drug to the brain for myelin repair in MS

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

Search for remyelinating therapies: removing the fibronectin obstacle

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

Why MS lesion resolve better in grey matter than in the white matter of the brain

INVESTIGATORS – Dennis Lentferink, Bart Eggen and Wia Baron

PROJECT – This project investigates why MS lesions are repaired better in the grey matter compared to the white matter of the brain. We argue that this is not only due to differences in the local micro-environment of the grey and white matter, but that this is also at least partially due to regional differences in the cells that repair MS lesions, the oligodendrocyte progenitor cells. By comparing these cells from the grey and white matter we anticipate to learn more about the repair process of MS, remyelination. When we know why certain cells are better equipped to regenerate myelin, we may design new tools that may help progenitor cells to restore MS lesions independent of the region.

Supported by a GSMS PhD fellowship

Grey and white matter astrocytes and their potential distinct role in remyelination

INVESTIGATORS – Inge Werkman and Wia Baron

PROJECT – In the brain and spinal cord of MS patients the isolating layer around nerve cells is damaged. This isolating layer is called myelin, which is produced by specialized cells called oligodendrocytes. After myelin loss, new myelin can be formed by newly formed oligodendrocytes during a process called remyelination. This is a highly-regulated process which requires signaling events that change overtime. Another type of cells in the brain called astrocytes are largely responsible for regulating remyelination. Surprisingly, the formation of new myelin seems faster and more efficient in the grey matter of the brain compared to the white matter. In this project, we investigate whether astrocytes differ between the grey and white matter and whether these differences are a cause for the observed enhanced remyelination in the grey matter. In addition, we study whether inflammation affects the astrocytes to regulate remyelination.

Supported by a GSMS PhD fellowship

In search of difference between myelin-producing cells

INVESTIGATORS – Jacomien Jongsma and Wia Baron

PROJECT – Multiple Sclerosis is a highly disabling disorder in which the isolation layer around nerve cells (called myelin) is broken down. In the central nervous system myelin is produced by oligodendrocytes and to regenerate myelin, newly-formed oligodendrocytes have to migrate to the lesion site and enwrap the bare nerve fibers. In MS, regeneration of myelin seems faster in the grey matter than in the white matter of the brain. To determine why this difference exists, and if we can use this difference to our advantage in the battle against this disease, we aim to identify differential responses of oligodendrocytes from the grey- and the white matter towards MS-relevant inflammatory mediators. In addition, we will investigate whether oligodendrocytes derived from people with and without differ in their reactions to harmful and helpful signals for remyelination.

Supported by a MD/PhD fellowship

Figure

Nerve cells in the brain and spinal cord are surrounded by myelin produced by oligodendrocytes, which are lost during demyelination. New myelin can be formed by newly-formed oligodendrocytes during remyelination which is regulated by astrocytes.

In search of differences between myelin-producing cells

Investigators – Jacomien Jongsma and Wia Baron

Project: Multiple Sclerosis is a highly disabling disorder in which the isolation layer around nerve cells (called myelin) is broken down. In the central nervous system myelin is produced by oligodendrocytes and to regenerate myelin, newly-formed oligodendrocytes have to migrate to the lesion site and enwrap the bare nerve fibers. In MS, regeneration of myelin seems faster in the grey matter than in the white matter of the brain. To determine why this difference exists, and if we can use this difference to our advantage in the battle against this disease, we aim to identify differential responses of oligodendrocytes from the grey- and the white matter towards MS-relevant inflammatory mediators. In addition, we will investigate whether oligodendrocytes derived from people with and without MS differ in their reactions to harmful and helpful signals for remyelination.

Supported by a MD/PhD fellowship

TNFR2 as a target for MS treatment.

Investigators – Valentina Pegoretti, Wia Baron, Jon Laman, Ulrich Eisel

Project: Tumor necrosis factor alpha (TNFα) is an important molecule that regulates many functions in our body. Importantly, TNFα modulates inflammatory responses and general homeostasis and has both beneficial and detrimental effects depending on the receptor that it activates. More specifically, TNF receptor 1 (TNFR1) activation leads to inflammation and tissue damage while TNF receptor 2 (TNFR2) activation has anti-inflammatory and tissue protective properties. Given these functions, TNFR2 is a potential drug candidate for therapeutic treatment of multiple sclerosis (MS). In this project, we examine whether activation of TNFR2 can be used for therapeutic intervention in mouse models of MS. To this end, we will elucidate the role of TNFR2 in remyelination and inflammation.  We anticipate to show that activation of TNFR2 is of therapeutic value for people with MS.

Supported by the Dutch MS Research Foundation

Cellular environment

Research on modulation of the cellular environment addresses the contributions of local immune cells, the microglia, as well as astrocytes, to brain tissue remodeling and repair. We recently obtained evidence that during the early phase of demyelination microglia assume a tissue-supportive phenotype that may be involved in tissue remodelling and remyelination. Further research on factors that induce this microglia phenotype, including appropriate neuronal and ECM factors (molecular environment), will pave the way for creating an environment permissive for remyelination of MS lesions.

Projects

The role of microglia in multiple sclerosis lesions

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

Unravelling the role of microglia in MS lesion progression from a single-cell perspective

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)

 

The role of microglial autophagy in Multiple Sclerosis

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

The role of microglia, the CNS-resident immune cells, in the MS (lesion) progression.

INVESTIGATORS – Corien Grit, Bart Eggen and Erik Boddeke

PROJECT – Despite out extensive knowledge about MS, little is known about the progressive stage of the disease. In this project, changes in gene expression patterns are studied in post mortem brain tissue of MS patients, in areas which appear to be normal and in which the myelin is still intact. This might provide clues about the processes during the progression of MS. In addition, the functions of microglia, the resident immune cells of the central nervous system, are examined especially during the progressive phase of MS using mouse models for MS.

Supported by the Dutch MS Research Foundation

The negative checkpoint regulator VISTA for MS immunotherapy by driving T-cell unresponsiveness

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

Cellular heterogeneity and cell-cell interactions in the development and progression of MS lesions

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