The Cell Biology of Remyelination

The failure of the endogenous regenerative process – remyelination - in chronic Multiple Sclerosis (MS) lesions leaves axons denuded of myelin and contributes to the neurodegeneration that underlies the progressive disability associated with the disease. Stimulating effective remyelination is therefore a key goal for regenerative medicine. Neuropathological studies in humans and animal models have shown that remyelination results in short, thin myelin sheaths predicted to be less efficient at accelerating conduction and providing axonal metabolic support - two key functions of the myelin sheath. To this end, this project examines intrinsic and extrinsic mechanisms that might explain these short, thin sheaths. We propose that they result from a combination of altered intrinsic and extrinsic pathways affecting the myelination process. Intrinsic pathways will be revealed by an innovative three-dimensional culture system using artificial axons developed in the laboratory of the host investigator, enabling changes associating with ageing to be revealed, whilst extrinsic pathways will be revealed using a genetic approach that allows the visualization of newly-generated myelin-forming cells (oligodendrocytes) and their myelin sheaths in demyelinated lesions of mice. These studies on the extrinsic pathway focus on the role of axonal activity, using chemogenetics to activate or inhibit axonal activity focally and rehabilitation to activate the system more globally. Together these experimental approaches will identify the causes for altered sheath geometry in remyelination, with these new discoveries then underpinning future studies targeting these pathways so as to enhance remyelination.

This project, which is heavily dependent on the use of animal models, was severely delayed due to the covid pandemic and associated research delays. Although all the proposed experiments have now been conducted, analysis is still underway and therefore only preliminary results have been obtained to date. This work is currently being completed and the results will be published in a timely manner.

In this project, I have examined the potential intrinsic and extrinsic influences on myelin sheath formation and maturation in young and adult oligodendroglia to which the results will have extensive applications. Nearly all available in vitro data on myelin sheath formation are derived from oligodendroglia isolated from heathy neonates, and few studies have attempted to distinguish between intrinsic (glial) and extrinsic (axonal) myelinating cues in the context of remyelination.

This project takes a multidisciplinary approach to the problem of myelin repair. The work completed to date includes a potent combination of in vivo and in vitro assays, incorporating molecular biology, histology, transgenics, light microscopy and EM, rehabilitation, and behavioural testing. This innovative project has created and optimized techniques with extensive application across regenerative medicine research, including 3-D cell culture, chemogenetics, and 3D imaging. The power of this project is in its broad applicability: the benefits of myelin repair extend well beyond Multiple Sclerosis (MS), to spinal cord injury (SCI), and to brain injury and disease. From my own experience as a person living with a mobility impairment, I know that even small improvements in axonal conduction can result in return of function and dramatic improvements in quality of life. By characterizing the causes for altered sheath geometry in remyelination, I will inform strategies to discover and deliver regenerative therapies in the brain.

Periodic Reporting for period 1 - ReMyelin (The Cell Biology of Remyelination)

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