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Regenerating CNS myelin — from mechanisms to experimental medicines
Open accessAbstract
Although the core concept of remyelination - based on the activation, migration, proliferation and differentiation of CNS progenitors - has not changed over the past 20 years, our understanding of the detailed mechanisms that underlie this process has developed considerably. We can now decorate the central events of remyelination with a host of pathways, molecules, mediators and cells, revealing a complex and precisely orchestrated process. These advances have led to recent drug-based and cell-based clinical trials for myelin diseases and have opened up hitherto unrecognized opportunities for drug-based approaches to therapeutically enhance remyelination.
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“Efficient myelin debris removal and clearance by phagocytic cells are critical to eliminate inhibitory signals interfering with OPC activation, recruitment to the site of demyelination and/or differentiation into myelinating mature OLs [14, 26, 27].”
From TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis (2020) · cites this paper as [14]
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“Central nervous system (CNS) remyelination reinstates axon health/ function1, yet fails in prevalent neurodegenerative disorders contributing to axon dysfunction/loss for which there is an unmet therapeutic need.”
From Central nervous system regeneration is driven by microglia necroptosis and repopulation (2019) · cites this paper as [1]
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Self-citationThe adult oligodendrocyte can participate in remyelination
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“correlating with white matter hyperintensities seen by MRI scans of patients [127], and myelin loss both reduces axon conduction velocities and leaves axons vulnerable to degradation and damage (reviewed in [128]).”
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“functional recovery of patients with long-standing and progressive disease (1).”
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“Consequently, remyelination strategies are being pursued in diseases such as multiple sclerosis (MS) with the hope of not only recovering nerve conduction in the short term but also protecting axons against degeneration in the long term (Franklin et al., 2012; Franklin and Ffrench-Constant, 2017; Lubetzki et al., 2020…”
BackgroundMultiple sclerosis: molecular pathogenesis and therapeutic intervention
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“The myelin sheath is formed by mature myelin-producing oligodendrocytes, and WM damage is caused by the loss of mature myelin-producing oligodendrocytes [36].”
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“Why then, is repair after CNS insult not sustained, as evidenced by the majority of MS lesions being of the chronic demyelinating type [27]? The reasons for remyelination failure are not well understood [28].”
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“Interestingly, differences in the extent of myelin regeneration can be observed between individual lesions and patients, potentially indicating heterogeneity within the OPC population and the mechanisms underlying failing myelin repair in any given patient [8].”
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Self-citationOligodendrocyte-encoded Kir4.1 function is required for axonal integrity
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Self-citationChanges in the Oligodendrocyte Progenitor Cell Proteome with Ageing
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“three ages were selected for the following reasons: (1) devel-”
BackgroundSelf-citationGlial cell alterations in diabetes-induced neurodegeneration
Llorián‐Salvador, M., Cabeza‐Fernández, S., Gomez-Sanchez, J. A., & de la Fuente, A. G. (2024) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-05024-y · Cited by 100
“Myelin loss is generally rapidly restored through a process known as remyelination, a regenerative process by which OPCs respond to myelin damage differentiating into myelinating oligodendrocytes and restabilizing myelin around denuded CNS axons [106].”
BackgroundOligodendrocyte progenitor cells in Alzheimer's disease: from physiology to pathology
Zou, P., Wu, C., Liu, T. C.-Y., Duan, R., & Yang, L. (2023) · Translational Neurodegeneration · doi:10.1186/s40035-023-00385-7 · Cited by 97
“However, the nOPCs generate new oligodendrocytes for myelination, and the aOPCs generate that for remyelination [59, 60].”
BackgroundEpigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility
Meijer, M., Agirre, E., Kabbe, M., van Tuijn, C. A., Heskol, A., Zheng, C., Mendanha Falcão, A., Bartosovic, M., Kirby, L., Calini, D., et al. (2022) · Neuron · doi:10.1016/j.neuron.2021.12.034 · Cited by 98
“Oligodendrocyte precursor cells (OPCs) in the adult CNS are recruited to MS lesions and are thought to contribute to remyelination during disease remission (Franklin and Ffrench-Constant, 2017), although this capacity is hindered upon disease progression (Jäkel et al., 2019; Yeung et al., 2019).”
BackgroundInsights into myelin dysfunction in schizophrenia and bipolar disorder
Valdés‐Tovar, M., Rodríguez‐Ramírez, A. M., Rodríguez-Cárdenas, L., Sotelo-Ramírez, C. E., Camarena, B., Sanabrais‐Jiménez, M. A., Solís‐Chagoyán, H., Argueta, J., & López-Riquelme, G. O. (2022) · World Journal of Psychiatry · doi:10.5498/wjp.v12.i2.264 · Cited by 96
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“In contrast to typical chemical demyelination models which have a single wave of OPC proliferation, differentiation and typically complete remyelination (Blakemore & Franklin, 2008; Franklin & ffrench-Constant, 2017), OPC proliferation and new oligodendrocyte formation continue for weeks after SCI.”
ResultLipids in regulating oligodendrocyte structure and function
Montani, L. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.07.016 · Cited by 99
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Myelination-independent functions of oligodendrocyte precursor cells in health and disease
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“Once differentiated, mature oligodendrocytes will engage with demyelinated axons and re-ensheath these axons with myelin to restore neurological function and neuroprotection 58 .”
Qian, Z., Li, H., Yang, H., Yang, Q., Lu, Z., Wang, L., Chen, Y., & Li, X. (2021) · Science Advances · doi:10.1126/sciadv.abi5811 · Cited by 93
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“However, it is now clear that OPCs and neural stem cells present in the CNS throughout life can generate new oligodendrocytes following damage to myelin, and that these cells can in turn regenerate myelin through the process of remyelination (Franklin and ffrench-Constant, 2017; Prineas and Connell, 1979; Samanta et a…”
BackgroundInfluentialHou, J., Zhou, Y., Cai, Z., Terekhova, M., Swain, A., Andhey, P. S., Guimaraes, R. M., Ulezko Antonova, A., Qiu, T., Sviben, S., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112293 · Cited by 85
Diet-dependent regulation of TGFβ impairs reparative innate immune responses after demyelination
Bosch-Queralt, M., Cantuti-Castelvetri, L., Damkou, A., Schifferer, M., Schlepckow, K., Alexopoulos, I., Lütjohann, D., Klose, C., Vaculčiaková, L., Masuda, T., et al. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00341-7 · Cited by 88
Naturally Occurring Nervonic Acid Ester Improves Myelin Synthesis by Human Oligodendrocytes
Lewkowicz, N., Piątek, P., Namiecińska, M., Domowicz, M., Bonikowski, R., Szemraj, J., Przygodzka, P., Stasiołek, M., & Lewkowicz, P. (2019) · Cells · doi:10.3390/cells8080786 · Cited by 86
“During the physiological reconstitution of CNS, OPCs, being abundant throughout the gray matter of CNS, migrate toward demyelinating plaque, where they can generate new OLs [29].”
BackgroundMyelin plasticity in adulthood and aging
Chapman, T. W., & Hill, R. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134645 · Cited by 101
“Chronic stages of multiple sclerosis are characterized by incomplete remyelination [104] presumably due to the inability of NG2 glia to differentiate [99].”
BackgroundOsorio-Querejeta, I., Carregal-Romero, S., Ayerdi-Izquierdo, A., Mäger, I., Nash, L. A., Wood, M., Egimendia, A., Betanzos, M., Alberro, A., Iparraguirre, L., et al. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12020186 · Cited by 85
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“These harmful events trigger a spontaneous repair process, known as remyelination, during which the oligodendrocyte precursor cells (OPCs), that persist in a quiescent state within the adult CNS [4,5], are activated, migrate, and differentiate to replace the OLs lost during pathological conditions [6].”
BackgroundCalcium Signaling in the Oligodendrocyte Lineage: Regulators and Consequences
Paez, P. M., & Lyons, D. A. (2020) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-100719-093305 · Cited by 83
“Numerous studies have indicated that the mechanisms that drive normal oligodendrocyte lineage progression through myelination are often essential for the regeneration of myelin (remyelination) following its loss or damage in disease or injury (Franklin & ffrench-Constant 2017).”
BackgroundInfluentialCentral Nervous System Remyelination: Roles of Glia and Innate Immune Cells
Baaklini, C. S., Rawji, K. S., Duncan, G. J., Ho, M. F. S., & Plemel, J. R. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00225 · Cited by 88
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The Role of Astrocytes in Remyelination
Rawji, K. S., Martinez, G. A. G., Sharma, A., & Franklin, R. J. M. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.05.006 · Cited by 84
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“The regeneration of myelin-forming OLs and the remyelination of functional axons are essential steps for the restoration of white matter integrity.(43) In addition to its well-known anti-inflammatory effects, our previous study identified a new function of IL-4 in the direct stimulation of OPC differentiation into mat…”
BackgroundMechanisms of axonal support by oligodendrocyte-derived extracellular vesicles
Krämer‐Albers, E., & Werner, H. B. (2023) · Nature reviews. Neuroscience · doi:10.1038/s41583-023-00711-y · Cited by 83
Galectin-3-Mediated Glial Crosstalk Drives Oligodendrocyte Differentiation and (Re)myelination
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Astrocytes in myelination and remyelination
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“Successful remyelination requires OPC proliferation, migration, differentiation to oligodendrocytes, and finally, maturation into myelinating oligodendrocytes (Franklin and Ffrench-Constant, 2017).”
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“Together with therapies targeting primary causes of demyelination, many research efforts have focused on promoting the regenerative potential of myelinating glia and their progenitors (Plemel et al., 2017; Stangel et al., 2017; Franklin and ffrench-Constant, 2017).”
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Remyelination by surviving oligodendrocytes is inefficient in the inflamed mammalian cortex
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Microglia Diversity in Health and Multiple Sclerosis
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Oligodendrocyte Differentiation and Myelination Is Potentiated via GABAB Receptor Activation
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Scaffold-Mediated Sustained, Non-viral Delivery of miR-219/miR-338 Promotes CNS Remyelination
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“27 No 2 Februar in axons cannot occur, which in turn results in perturbed axonal transport, degeneration, and ultimately functional impairment.(4) The importance of this structure was further displayed in patients with non-penetrating traumatic nerve injuries in the CNS, where even though a portion of axons was spared…”
BackgroundSelf-citationAndrovic, P., Schifferer, M., Perez Anderson, K., Cantuti-Castelvetri, L., Jiang, H., Ji, H., Liu, L., Gouna, G., Berghoff, S. A., Besson-Girard, S., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39447-9 · Cited by 67
Chen, C. Z.-Y., Neumann, B., Förster, S., & Franklin, R. J. M. (2021) · Open Biology · doi:10.1098/rsob.200352 · Cited by 66
“Remyelination of central axons reverses conduction deficits and protects axons from secondary degeneration [5]; however, whether oligodendrocyte- or SC-mediated remyelination can achieve this to equal degrees is not known.”
BackgroundSelf-citationWang, X., Chang, L., Wan, X., Tan, Y., Qu, Y., Shan, J., Yang, Y. H., Ma, L., & Hashimoto, K. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105635 · Cited by 67
“After CPZ withdrawal, spontaneous remyelination was shown in CPZ-treated mice (Franklin and Ffrench-Constant, 2017; Torkildsen et al., 2008).”
Background
Metadata
- Authors
- Franklin, R. J. M., & ffrench-Constant, C.
- Affiliations
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Corresponding author
- Franklin, Robin J. M.
- Venue
- Nature Reviews Neuroscience
- Published
- 2017-11-16
- Volume
- 18
- Issue
- 12
- Pages
- 753-769
- ISSN
- 1471-003X (ISSN-L)
- 1471-0048
- OpenAlex
- W2770653478
- Semantic Scholar
- 873fe364632a01af9b64b05352afae59ba7235e0
- Cited by
- 647
- References
- 222
- Citations by year
- 2026: 84 · 2025: 72 · 2024: 84 · 2023: 58 · 2022: 83 · 2021: 83 · 2020: 70 · 2019: 79 · 2018: 33 · 2017: 1
- FWCI
- 7.99
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust (104783/Z/14/Z)
- Medical Research Council (MC_PC_12009)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Keywords
- remyelination, central nervous system myelin, multiple sclerosis, demyelination, oligodendrocyte precursor cells, cell therapy, myelin diseases
- MeSH terms
- Animals, Cell Differentiation, Central Nervous System, Demyelinating Diseases, Humans, Myelin Sheath, Nerve Regeneration, Oligodendroglia
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