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An MRI-informed histo-molecular analysis implicates ependymal cells in the pathogenesis of periventricular pathology in multiple sclerosis

病理 多发性硬化 发病机制 医学 神经科学 生物 免疫学
作者
Adam M.R. Groh,Elia Afanasiev,Risavarshni Thevakumaran,Liam Callahan‐Martin,Finn Creeggan,Moein Yaqubi,Stéphanie Zandee,Alexandre Prat,David A. Rudko,Jo Anne Stratton
标识
DOI:10.1101/2025.01.14.633055
摘要

Abstract It is now widely recognized that the cerebrospinal fluid (CSF)-adjacent brain surfaces – namely the subpial cortical region and the ependyma-adjacent periventricular region – are uniquely susceptible to a distinct, diffuse form of pathology in multiple sclerosis. So-called surface-in gradients of pathology predict future disease relapses independent of classical white matter lesions and are thought to occur as a result of cytotoxic factors in the CSF. Given the underlying mechanisms driving surface-in gradients appear to be distinct, they represent a novel treatment target. However, exactly how cytotoxic factor entry into the brain is regulated at these CSF-facing borders is not understood, particularly at the ventricular interface. Indeed, although studies have indicated that ependymal cells may be damaged in MS, there has yet to be a comprehensive assessment of cell health in the disease. We employed ultra-high-field MRI-guided immunohistochemistry, electron microscopy, and multiomic single nucleus RNA/ATAC sequencing to deeply phenotype human ependymal cells in MS. Our data revealed that ependymal cell pathology is a direct correlate of periventricular surface-in gradients of pathology in MS, and that the immune-responsive, reactive state assumed by ependymal cells is associated with widespread transporter and junctional protein gene dysregulation. We then further defined the gene regulatory networks underpinning the MS ependymal state, predicted ligands known to be enriched in MS CSF that could drive the emergence of this state, and tested one candidate in vivo . We found that IFNγ increased murine ependymal permeability and that conditional knockout of ependymal interferon gamma receptor 1 (Ifngr1) was sufficient to reverse this effect. Our data directly implicate ependymal cell dysregulation in the emergence of periventricular pathology in MS. More widely, we denote the modulatory capacity of CSF ligands on ependymal cell function and how this may influence the inflammatory status of the periventricular region.

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