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Despite the availability of various treatments for relapsing-remitting multiple sclerosis (MS), the progressive phase of the disease remains difficult to treat due to a lack of understanding of the mechanisms that drive disease progression. New concepts suggest that persistent inflammation in the central nervous system and a gradual failure of compensatory mechanisms, including remyelination, contribute to disease progression. While promoting remyelination presents a promising approach, it remains an unmet need in MS treatment, indicating that the mechanisms of remyelination and failure differ between humans and animal models. New technologies allow for investigating the cellular and molecular mechanisms underlying remyelination failure in human tissue samples. This review aims to summarize our current knowledge of mechanisms of remyelination and failure, identify open questions, challenge existing concepts, and discuss strategies to overcome the translational roadblock in remyelination-promoting therapies.
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