Multiple sclerosis

Multiple sclerosis (MS) affects nerves in the brain and spinal cord. Each nerve fibre in the brain and spinal cord is surrounded by a layer of protein called myelin, which protects the nerve and helps electrical signals from the brain travel to the rest of the body. In MS, the myelin becomes damaged. This disrupts the transfer of these nerve signals, causing a wide range of potential symptoms, such as loss of vision, uncontrolled muscle movements, difficulties with balance and co-ordination, and fatigue. In addition to the myelin sheath covering being damaged, MS can also damage the underlying nerve fibre called axons. It is thought that axonal damage is the main cause of disability and disease progression in MS.

Models

Myelination models have been developed using Mimetix aligned fibres as model axons. The Mimetix aligned fibre scaffold supports:

  • the differentiation of more than 80% of oligodendrocyte precursors into mature oligodendrocytes in 14 days
  • myelination – the production of sheath lengths comparable to in vivo situation within 7 days by 90% of the oligodendrocytes
  • the physical guidance and support for Schwann cells
Oligodendrocytes provide support to axons and produce myelin sheaths which insulate axons. Oligodendrocytes form segments of myelin sheaths of several neurons at once.
Mimetix aligned PLLA fibres of 2 micron diameter are incorporated into different well plate formats (SEM)
Cortical oligodendrocyte precursors differentiate into active oligodendrocytes and lay myelin on the Mimetix scaffold in the absence of neurons. Cells are stained after 14 days with myelin basic protein (green) and Hoechst (blue).
Oligodendrocyte precursors (NG2) and oligodendrocytes (MBP). More than 600 cells were counted per condition. Mean and standard deviation are shown for three experiments.
Schwann cells were grown for 21 days and stained with anti S-100 (purple) and Hoechst (blue)

Ref: M. Bechler, L. Byrne, C. Ffrench-Constant, “CNS Myelin Sheaths are an instrinsic property of Oligodendrocytes”. Current Biology 25, 1-6 September 21, 2015

Dr Marie Bechler, a senior researcher in the ffrench-Constant laboratory at the MRC Centre for Regenerative Medicine, said “The aligned Mimetix scaffold fibres have been an invaluable tool, allowing us to answer fundamental questions regarding how oligodendrocytes form central nervous system (CNS) myelin sheaths. The suppliers of the Mimetix fibres worked with us to create customised three-dimensional fibres, facilitating the development of an oligodendrocyte culture assay. The culture system we developed permits the examination of myelin sheath formation in the absence of neurons. The aligned microfibres used in our research have enabled us to examine both the physical and molecular signals sufficient to drive CNS myelin sheath formation, which could not be assessed in other culture models. This has opened new opportunities to examine the role of physical cues, heterogeneity due to oligodendrocyte origin, and the sufficiency of molecules to control the number and size of myelin sheaths formed by oligodendrocytes. Our findings and future work illuminate how myelin sheaths are formed during brain and spinal cord development as well as what signals enhance myelin sheath formation. This research is of particular importance for developing future therapies for diseases of myelin loss, such as multiple sclerosis and leukodystrophies”.

Dr Bechler

Myelination Publications

Luo, J. X. X., Cui, Q.,Yaqubi M.,Hall, J.A., Dudley, R., Srour, M., Addour, N., Jamann, H., Larochelle, C., Blain, M., Healy, L. M., Stratton J. A., Sonnen, J. A., Kennedy T. E., Antel, J.P. Human Oligodendrocyte Myelination Potential; Relation to Age and Differentiation. Annals of Neurology. 91(2), 178-191 (2021)

Swire, M., Assinck, P., McNaughton, P. A., Lyons, D. A., ffrench-Constant, C. & Livesey, M. R. Oligodendrocyte HCN2 Channels Regulate Myelin Sheath Length. Journal of Neuroscience 41 (38), 7954-7964 (2021).

Esmonde-White, C., Yaqubi, M., Bilodeau, P., Cui, Q., Pernin, F., Larochelle, C., Ghadiri, M., Xu, Y., Kennedy, T., Hall, J., Healy, L. & Antel, J. Distinct Function-Related Molecular Profile of Adult Human A2B5-Positive Pre-Oligodendrocytes Versus Mature Oligodendrocytes. Journal of Neuropathology & Experimental Neurology 78, 468-479 (2019).

Swire, M., Kotelevtsev, Y., Webb, D., Lyons, D. & ffrench-Constant, C. Endothelin signalling mediates experience-dependent myelination in the CNS. eLife 8, (2019).

Bechler, M. A Neuron-Free Microfiber Assay to Assess Myelin Sheath Formation.Oligodendrocytes 97-110 (2019). doi:10.1007/978-1-4939-9072-6_6

Allimuthu, D., Hubler, Z., Najm, F., Tang, H., Bederman, I., Seibel, W., Tesar, P. & Adams, D. Diverse Chemical Scaffolds Enhance Oligodendrocyte Formation by Inhibiting CYP51, TM7SF2, or EBP. Cell Chemical Biology 26, 593-599.e4 (2019).

Fu, M., McAlear, T., Nguyen, H., Oses-Prieto, J., Valenzuela, A., Shi, R., Perrino, J., Huang, T., Burlingame, A., Bechstedt, S. & Barres, B. The Golgi Outpost Protein TPPP Nucleates Microtubules and Is Critical for Myelination. Cell 179, 132-146.e14 (2019).

Xu, Y., Chitsaz, D., Brown, R., Cui, Q., Dabarno, M., Antel, J. & Kennedy, T. Deep learning for high-throughput quantification of oligodendrocyte ensheathment at single-cell resolution. Communications Biology 2, (2019). Read More

Malheiro, A., Correia, B., Ferreira da Silva, T., Bessa‐Neto, D., Van Veldhoven, P. & Brites, P. Leukodystrophy caused by plasmalogen deficiency rescued by glyceryl 1‐myristyl ether treatment. Brain Pathology 29, 622-639 (2019).

Dillenburg, A., Ireland, G., Holloway, R., Davies, C., Evans, F., Swire, M., Bechler, M., Soong, D., Yuen, T., Su, G., Becher, J., Smith, C., Williams, A. & Miron, V. Activin receptors regulate the oligodendrocyte lineage in health and disease. Acta Neuropathologica 135, 887-906 (2018).

Ulc, A., Zeug, A., Bauch, J., van Leeuwen, S., Kuhlmann, T., ffrench-Constant, C., Ponimaskin, E. & Faissner, A. The guanine nucleotide exchange factor Vav3 modulates oligodendrocyte precursor differentiation and supports remyelination in white matter lesions. Glia 67, 376–392 (2018).

Harboe, M., Torvund-Jensen, J., Kjaer-Sorensen, K. & Laursen, L. S. Ephrin-A1-EphA4 signaling negatively regulates myelination in the central nervous system. Glia 66, 934–950 (2018).

Elitt, M., Shick, H., Madhavan, M., Allan, K., Clayton, B., Weng, C., Miller, T., Factor, D., Barbar, L., Nawash, B., Nevin, Z., Lager, A., Li, Y., Jin, F., Adams, D. & Tesar, P. Chemical Screening Identifies Enhancers of Mutant Oligodendrocyte Survival and Unmasks a Distinct Pathological Phase in Pelizaeus-Merzbacher Disease. Stem Cell Reports 11, 711-726 (2018).

Hubler, Z., Allimuthu, D., Bederman, I., Elitt, M., Madhavan, M., Allan, K., Shick, H., Garrison, E., T. Karl, M., Factor, D., Nevin, Z., Sax, J., Thompson, M., Fedorov, Y., Jin, J., Wilson, W., Giera, M., Bracher, F., Miller, R., Tesar, P. & Adams, D. Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination. Nature 560, 372-376 (2018). Read More

Li, L., Tian, E., Chen, X., Chao, J., Klein, J., Qu, Q., Sun, G., Sun, G., Huang, Y., Warden, C., Ye, P., Feng, L., Li, X., Cui, Q., Sultan, A., Douvaras, P., Fossati, V., Sanjana, N., Riggs, A. & Shi, Y. GFAP Mutations in Astrocytes Impair Oligodendrocyte Progenitor Proliferation and Myelination in an hiPSC Model of Alexander Disease. Cell Stem Cell 23, 239-251.e6 (2018).

Jadasz, J., Tepe, L., Beyer, F., Samper Agrelo, I., Akkermann, R., Spitzhorn, L., Silva, M., Oreffo, R., Hartung, H., Prigione, A., Rivera, F., Adjaye, J. & Küry, P.  Human mesenchymal factors induce rat hippocampal- and human neural stem cell dependent oligodendrogenesis. Glia 66, 145–160 (2017).

Bechler, M., Byrne, L. & ffrench-Constant, C. CNS Myelin Sheath Lengths Are an Intrinsic Property of Oligodendrocytes. Current Biology 25, 2411-2416 (2015). Read More