Donders Institute for Brain, Cognition and Behaviour
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Thesis defense Kim de Kleijn (Donders series 576)

15 December 2022

Promotor: prof. dr. G. Martens

Human brain cell and organoid models to explore the neuropathology of multiple sclerosis

There is a high disease burden for patients suffering from multiple sclerosis (MS), a neurodegenerative disease with an inflammatory component. The current treatment options are restricted to medications that reduce symptoms of the relapsing-remitting variant of MS, but do not halt disease progression. Two recent developments within the field of MS will aid in the design of new and more effective disease-modifying therapies, namely 1) more focus on the brain instead of the peripheral immune system as the origin of disease etiology (the “inside-out” hypothesis), and 2) generation of three-dimensional (3D) models for the human brain. In this thesis, I have therefore explored the “inside-out” hypothesis, evaluated existing in vitro models for MS and their applicability for studying this disease, and developed a new 3D human brain organoid model with a high diversity of innately growing cell types, e.g. to examine neuroinflammation in the context of neurodegenerative diseases. My results provide a stepping stone for a novel approach towards studying MS etiology in the brain and may provide new targets for disease-modifying therapies for neurodegenerative diseases such as MS.