A comparative transcriptomic analysis of mouse demyelination models and Multiple Sclerosis lesions

Abstract Demyelinating diseases are debilitating conditions characterized by loss of the myelin sheaths, ultimately leading to neurodegeneration. Toxicity models are among the most commonly used mouse models to induce demyelination; however, it remains unclear whether different demyelination models elicit distinct glial responses, and how comparable these changes are to human diseases like Multiple Sclerosis (MS). To address this gap, we integrated new and published single cell transcriptomic data of the subcortical white matter from lysophosphatidylcholine (LPC) and cuprizone (CPZ) toxicity models, and compared them to an existing human MS dataset. We find that CPZ demyelination induces a distinct oligodendrocyte (OL) state, enriched for cell stress pathways and C dkn1a and Nupr1 expression, that resembles disease-associated OLs in MS lesions. However, both LPC and CPZ converge at a similar remyelination OL state that expresses immune-related genes, such as Socs3 and B2m . Analysis of microglia reveals a largely conserved activation of microglia in both models, but LPC demyelination induces a stronger response, with recruitment of perivascular macrophages, that persists longer during remyelination. Interestingly, both mouse models do not recapitulate the heterogeneity of microglia across different MS lesion types. Overall, this comparative analysis uncovers specific gene expression differences between mouse demyelination models and human MS lesions, providing a foundation for using the animal models effectively to advance remyelination therapies.