Microglia-associated progression of multiple sclerosis: target identification and therapeutic engagement in human in vitro models

Chronic progression of multiple sclerosis (MS) is likely to develop on the basis of a highly complex interaction of different mechanisms, which are probably already present at disease onset. While animal models have been instrumental in developing therapies for relapsing forms of MS, they have provided limited insight into the processes driving disease progression. To overcome these limitations, human in vitro models have emerged as powerful tools to dissect cellular mechanisms and identify novel therapeutic targets. Here, we highlight advances in modeling MS progression, using human induced pluripotent stem cell-derived systems, with a particular focus on microglia as key mediators of neuroinflammation and neurodegeneration. We critically discuss the strengths and limitations of current induced pluripotent stem cell-based microglia models, and their utility in target identification and therapeutic engagement. By emphasizing translational applications and methodological innovations, this Review provides a framework for leveraging human in vitro models to better understand and therapeutically modulate microglia-associated progression in MS.