Distinct transcriptional changes distinguish efficient and poor remyelination in multiple sclerosis

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Multiple sclerosis (MS) is characterized by heterogeneous remyelination potential.
• The molecular mechanisms driving remyelination capacity remain largely unknown.
• Understanding these mechanisms is crucial for developing effective MS therapies.

Purpose of the Study:

• To identify molecular signatures associated with varying remyelination capacity in MS.
• To uncover known and novel pro-remyelinating molecules for therapeutic development.
• To stratify MS donors based on remyelination efficiency to dissect molecular differences.

Main Methods:

• Stratification of MS donors (n=239) into efficiently remyelinating donors (ERDs) and poorly remyelinating donors (PRDs).
• Bulk RNA sequencing of remyelinated lesions (RLs), active lesions (ALs non-foamy and foamy), and normal-appearing white matter (NAWM).
• Bioinformatics analysis to identify key pathways and upstream regulators.

Main Results:

• Active lesions with non-foamy microglia/macrophages correlated positively with remyelination.
• Efficient remyelination in ERDs was associated with upregulated epithelial-mesenchymal transition pathways.
• In PRDs, inflammation and damage-associated pathways were upregulated in foamy active lesions, potentially hindering remyelination.
• Identified known (e.g., CXCL12, EGF, TREM2) and novel (e.g., GDF10, CCN1, FGF10) pro-remyelinating molecules.

Conclusions:

• Microglia/macrophage state significantly influences remyelination potential in MS.
• Distinct molecular profiles exist between ERDs and PRDs, highlighting pathways like epithelial-mesenchymal transition.
• Identified therapeutic targets, including novel molecules, for promoting remyelination and improving clinical outcomes in MS.