Cerebrospinal fluid-driven ependymal motile cilia defects are implicated in multiple sclerosis

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Multiple sclerosis (MS) involves central nervous system (CNS) autoimmune attack, leading to demyelination and focal lesions.
• Diffuse surface-in pathology gradients suggest cerebrospinal fluid (CSF) factors contribute to MS progression, particularly in CSF-contacting areas.
• Ependymal cells, lining ventricles, possess motile cilia crucial for CSF homeostasis, but their role in MS remains unexplored.

Purpose of the Study:

• Investigate the role and impact of ependymal cell cilia in the context of multiple sclerosis (MS).
• Determine if ependymal cilia are dysregulated in MS patients and animal models.
• Evaluate the cellular and behavioral consequences of ependymal ciliary disruption in MS.

Main Methods:

• Single-cell RNA sequencing of human ependymal cells from MS patients and controls.
• Exposure of cultured rodent ependymal cells to MS patient CSF.
• Analysis of ependymal cilia in the experimental autoimmune encephalomyelitis (EAE) mouse model.
• Generation of a transgenic mouse model with conditional ependymal ciliary disruption.

Main Results:

• Single-cell RNA sequencing revealed significant dysregulation of ciliary genes in human ependymal cells from MS patients.
• MS patient CSF exposure altered ependymal cell ciliary gene/protein expression and reduced beating frequency.
• Ependymal cells in EAE models showed altered cilia gene and protein expression; IFNγ in MS CSF affected cilia motility.
• Conditional knockout of Ccdc39 in mouse ependymal cells caused ventricular enlargement, increased microglial density, and behavioral changes.

Conclusions:

• Motile cilia of ependymal cells are dysregulated in CNS autoimmunity, specifically in MS.
• Ependymal cilia disruption may contribute to periventricular pathology in MS.
• Disrupted ependymal cilia could underlie behavioral deficits and non-motor symptoms in MS.