Revisiting remyelination: Towards a consensus on the regeneration of CNS myelin
Open accessAbstract
The biology of CNS remyelination has attracted considerable interest in recent years because of its translational potential to yield regenerative therapies for the treatment of chronic and progressive demyelinating diseases such as multiple sclerosis (MS). Critical to devising myelin regenerative therapies is a detailed understanding of how remyelination occurs. The accepted dogma, based on animal studies, has been that the myelin sheaths of remyelination are made by oligodendrocytes newly generated from adult oligodendrocyte progenitor cells in a classical regenerative process of progenitor migration, proliferation and differentiation. However, recent human and a growing number of animal studies have revealed a second mode of remyelination in which mature oligodendrocytes surviving within an area of demyelination are able to regenerate new myelin sheaths. This discovery, while opening up new opportunities for therapeutic remyelination, has also raised the question of whether there are fundamental differences in myelin regeneration between humans and some of the species in which experimental remyelination studies are conducted. Here we review how this second mode of remyelination can be integrated into a wider and revised framework for understanding remyelination in which apparent species differences can be reconciled but that also raises important questions for future research.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Which cells are at the forefront of myelin regeneration is a matter of ongoing debate.
“Which cells are at the forefront of myelin regeneration is a matter of ongoing debate.44,45”
From BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis (2025) · cites this paper as [44]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Motor skill learning requires active central myelination
McKenzie, I. A., Ohayon, D., Li, H., Paes de Faria, J., Emery, B., Tohyama, K., & Richardson, W. D. (2014) · Science · doi:10.1126/science.1254960 · Cited by 1,177 · see citing works
Zawadzka, M., Rivers, L. E., Fancy, S. P. J., Zhao, C., Tripathi, R., Jamen, F., Young, K., Goncharevich, A., Pohl, H., Rizzi, M., et al. (2010) · Cell stem cell · doi:10.1016/j.stem.2010.04.002 · Cited by 650 · see citing works
Self-citationRejuvenation of Regeneration in the Aging Central Nervous System
Ruckh, J. M., Zhao, J.-W., Shadrach, J. L., van Wijngaarden, P., Rao, T. N., Wagers, A. J., & Franklin, R. J. M. (2012) · Cell Stem Cell · doi:10.1016/j.stem.2011.11.019 · Cited by 649 · see citing works
Self-citationRegenerating CNS myelin — from mechanisms to experimental medicines
Franklin, R. J. M., & ffrench-Constant, C. (2017) · Nature Reviews Neuroscience · doi:10.1038/nrn.2017.136 · Cited by 647 · see citing works
Self-citationDisease-specific oligodendrocyte lineage cells arise in multiple sclerosis
Falcão, A. M., van Bruggen, D., Marques, S., Meijer, M., Jäkel, S., Agirre, E., Samudyata, Floriddia, E. M., Vanichkina, D. P., ffrench-Constant, C., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0236-y · Cited by 579 · see citing works
Endogenous progenitors remyelinate demyelinated axons in the adult CNS
Gensert, J. M., & Goldman, J. E. (1997) · Neuron · doi:10.1016/s0896-6273(00)80359-1 · Cited by 544 · see citing works
Dynamics of Oligodendrocyte Generation and Myelination in the Human Brain
Yeung, M. S. Y., Zdunek, S., Bergmann, O., Bernard, S., Salehpour, M., Alkass, K., Perl, S., Tisdale, J., Possnert, G., Brundin, L., et al. (2014) · Cell · doi:10.1016/j.cell.2014.10.011 · Cited by 541 · see citing works
Self-citationKirby, L., Jin, J., Cardona, J. G., Smith, M. D., Martin, K. A., Wang, J., Strasburger, H., Herbst, L., Alexis, M., Karnell, J., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11638-3 · Cited by 436 · see citing works
Dynamics of oligodendrocyte generation in multiple sclerosis
Yeung, M. S. Y., Djelloul, M., Steiner, E., Bernard, S., Salehpour, M., Possnert, G., Brundin, L., & Frisén, J. (2019) · Nature · doi:10.1038/s41586-018-0842-3 · Cited by 376 · see citing works
Self-citationMyelin degeneration and diminished myelin renewal contribute to age-related deficits in memory
Wang, F., Ren, S.-Y., Chen, J.-F., Liu, K., Li, R.-X., Li, Z.-F., Hu, B., Niu, J.-Q., Xiao, L., Chan, J. R., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0588-8 · Cited by 348 · see citing works
Remyelination alters the pattern of myelin in the cerebral cortex
Orthmann-Murphy, J., Call, C. L., Molina-Castro, G. C., Hsieh, Y. C., Rasband, M. N., Calabresi, P. A., & Bergles, D. E. (2020) · eLife · doi:10.7554/elife.56621 · Cited by 111 · see citing works
Flagged first, then by citations
Research works printed but not linked: 40
- O. Périer, A. Grégoire, Electron microscopic features of multiple sclerosis lesions, Brain 88 (1965) 937-952, https://doi.org/10.1093/brain/88.5.937. · DOI
- A.J. Green, J.M. Gelfand, B.A. Cree, C. Bevan, W.J. Boscardin, F. Mei, J. Inman, S. Arnow, M. Devereux, A. Abounasr, H. Nobuta, A. Zhu, M. Friessen, R. Gerona, H. C. von Büdingen, R.G. Henry, S.L. Hauser, J.R. Chan, Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial, Lancet 390 (2017) 2481-2489, https://doi.org/ 10.1016/S0140-6736(17)32346-2. · DOI · Paper page
- S.A. Goldman, F. Nottebohm, Neuronal production, migration, and differentiation in a vocal control nucleus of the adult female canary brain, Proc. Natl. Acad. Sci. U. S. A. 80 (1983) 2390-2394, https://doi.org/10.1073/pnas.80.8.2390. · DOI
- C. ffrench-Constant, M.C. Raff, Proliferating bipotential glial progenitor cells in adult rat optic nerve, Nature 319 (1986) 499-502, https://doi.org/10.1038/ 319499a0. · DOI
- W.M. Carroll, A.R. Jennings, Early recruitment of oligodendrocyte precursors in CNS demyelination, Brain 117 (Pt 3) (1994) 563-578, https://doi.org/10.1093/ brain/117.3.563. · DOI · Paper page
- S.C. Zhang, B. Ge, I.D. Duncan, Adult brain retains the potential to generate oligodendroglial progenitors with extensive myelination capacity, Proc. Natl. Acad. Sci. U. S. A. 96 (1999) 4089-4094, https://doi.org/10.1073/pnas.96.7.4089. · DOI
- M.S. Windrem, M.C. Nunes, W.K. Rashbaum, T.H. Schwartz, R.A. Goodman, G. McKhann, N.S. Roy, S.A. Goldman, Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain, Nat. Med. 10 (2004) 93-97, https://doi.org/10.1038/nm974. · DOI · Paper page
- R.B. Tripathi, L.E. Rivers, K.M. Young, F. Jamen, W.D. Richardson, NG2 glia generate new oligodendrocytes but few astrocytes in a murine experimental autoimmune encephalomyelitis model of demyelinating disease, J. Neurosci. 30 (2010) 16383-16390, https://doi.org/10.1523/JNEUROSCI.3411-10.2010. · DOI · Paper page
- A.H. Crawford, R.B. Tripathi, W.D. Richardson, R.J.M. Franklin, Developmental origin of oligodendrocyte lineage cells determines response to demyelination and susceptibility to age-associated functional decline, Cell Rep. 15 (2016) 761-773, https://doi.org/10.1016/j.celrep.2016.03.069. · DOI
- B. Neumann, R. Baror, C. Zhao, M. Segel, S. Dietmann, K.S. Rawji, S. Foerster, C. R. McClain, K. Chalut, P. van Wijngaarden, R. Franklin, Metformin restores CNS remyelination capacity by rejuvenating aged stem cells, Cell Stem Cell 25 (2019) 473-485, https://doi.org/10.1016/j.stem.2019.08.015, e8. · DOI · Paper page
- A.H. Crawford, R.B. Tripathi, S. Foerster, I. McKenzie, E. Kougioumtzidou, M. Grist, W.D. Richardson, R. Franklin, Pre-existing mature oligodendrocytes do not contribute to remyelination following toxin-induced spinal cord demyelination, Am. J. Pathol. 186 (2016) 511-516, https://doi.org/10.1016/j. ajpath.2015.11.005. · DOI
- J.M. Williamson, D.A. Lyons, Myelin dynamics throughout life: an ever-changing landscape? Front. Cell Neurosci. 12 (2018) 424, https://doi.org/10.3389/ fncel.2018.00424. · DOI
- S.L. Bengtsson, Z. Nagy, S. Skare, L. Forsman, H. Forssberg, F. Ullén, Extensive piano practicing has regionally specific effects on white matter development, Nat. Neurosci. 8 (2005) 1148-1150, https://doi.org/10.1038/nn1516. · DOI · Paper page
- M. Lövdén, N.C. Bodammer, S. Kühn, J. Kaufmann, H. Schütze, C. Tempelmann, H. J. Heinze, E. Düzel, F. Schmiedek, U. Lindenberger, Experience-dependent plasticity of white-matter microstructure extends into old age, Neuropsychologia 48 (2010) 3878-3883, https://doi.org/10.1016/j.neuropsychologia.2010.08.026. · DOI · Paper page
- J. Scholz, M.C. Klein, T.E.J. Behrens, H. Johansen-Berg, Training induces changes in white-matter architecture, Nat. Neurosci. 12 (2009) 1370-1371, https://doi. org/10.1038/nn.2412. · DOI · Paper page
- B. Bodini, M. Veronese, D. García-Lorenzo, M. Battaglini, E. Poirion, A. Chardain, L. Freeman, C. Louapre, M. Tchikviladze, C. Papeix, F. Dollé, B. Zalc, C. Lubetzki, M. Bottlaender, F. Turkheimer, B. Stankoff, Dynamic imaging of individual remyelination profiles in multiple sclerosis, Ann. Neurol. 79 (2016) 726-738, https://doi.org/10.1002/ana.24620. · DOI
- E.G. Hughes, J.L. Orthmann-Murphy, A.J. Langseth, D.E. Bergles, Myelin remodeling through experience-dependent oligodendrogenesis in the adult somatosensory cortex, Nat. Neurosci. 468 (2018) 244-706, https://doi.org/ 10.1038/s41593-018-0121-5. · DOI · Paper page
- K.L. Spalding, R.D. Bhardwaj, B.A. Buchholz, H. Druid, J. Frisén, Retrospective birth dating of cells in humans, Cell 122 (2005) 133-143, https://doi.org/ 10.1016/j.cell.2005.04.028. · DOI
- B. Neumann, S. Foerster, C. Zhao, B. Bodini, D.S. Reich, D.E. Bergles, R. T. Káradóttir, C. Lubetzki, L.L. Lairson, B. Zalc, B. Stankoff, R. Franklin, Problems and pitfalls of identifying remyelination in multiple sclerosis, Cell Stem Cell 26 (2020) 617-619, https://doi.org/10.1016/j.stem.2020.03.017. · DOI
- S. Jäkel, E. Agirre, A. Mendanha Falcão, D. van Bruggen, K.W. Lee, I. Knuesel, D. Malhotra, C. ffrench-Constant, A. Williams, G. Castelo-Branco, Altered human oligodendrocyte heterogeneity in multiple sclerosis, Nature 566 (2019) 543-547, https://doi.org/10.1038/s41586-019-0903-2. · DOI · Paper page
- A.G. de la Fuente, R.M.L. Queiroz, T. Ghosh, C.E. McMurran, J.F. Cubillos, D. E. Bergles, D.C. Fitzgerald, C.A. Jones, K.S. Lilley, C.P. Glover, R. Franklin, Changes in the oligodendrocyte progenitor cell proteome with ageing, Mol. Cell Proteom. 19 (2020) 1281-1302, https://doi.org/10.1074/mcp.RA120.002102, mcp. RA120.002102. · DOI
- I.D. Duncan, A.B. Radcliff, M. Heidari, G. Kidd, B.K. August, L.A. Wierenga, The adult oligodendrocyte can participate in remyelination, Proc. Natl. Acad. Sci. U. S. A. 94 (2018), 201808064, https://doi.org/10.1073/pnas.1808064115. · DOI · Paper page
- C.M. Bacmeister, H.J. Barr, C.R. McClain, M.A. Thornton, D. Nettles, C.G. Welle, E. G. Hughes, Motor learning promotes remyelination via new and surviving oligodendrocytes, Nat. Neurosci. 378 (2020), 169-13, https://doi.org/10.1038/ s41593-020-0637-3. · DOI
- Neely, S.A., Williamson, J.M., Klingseisen, A., Zoupi, L., Early, J.J., Williams, A., et al., n.d. New oligodendrocytes exhibit more abundant andaccurate myelin regeneration than those that survive demyelination, https://doi.org/10.1101/20 20.05.22.110551. · DOI
- K. Heß, L. Starost, N.W. Kieran, C. Thomas, M.C.J. Vincenten, J. Antel, G. Martino, I. Huitinga, L. Healy, T. Kuhlmann, Lesion stage-dependent causes for impaired remyelination in MS, Acta Neuropathol. 140 (2020) 359-375, https://doi.org/ 10.1007/s00401-020-02189-9. · DOI
- E.G. Hughes, S.H. Kang, M. Fukaya, D.E. Bergles, Oligodendrocyte progenitors balance growth with self-repulsion to achieve homeostasis in the adult brain, Nat. Neurosci. 16 (2013) 668-676, https://doi.org/10.1038/nn.3390. · DOI · Paper page
- Foerster, S., Neumann, B., McClain, C.R., Di Canio, L., Chen, C.Z., Reich, D.S., et al., n.d. Proliferation is a requirement for differentiation of oligodendrocyte progenitor cells during CNS remyelination, https://doi.org/10.1101/2020.05.21. 108373. · DOI
- C. Habermacher, M.C. Angulo, N. Benamer, Glutamate versus GABA in neuron- oligodendroglia communication, Glia 67 (2019) 2092-2106, https://doi.org/ 10.1002/glia.23618. · DOI
- F. Viganò, W. Möbius, M. Götz, L. Dimou, Transplantation reveals regional differences in oligodendrocyte differentiation in the adult brain, Nat. Neurosci. 16 (2013) 1370-1372, https://doi.org/10.1038/nn.3503. · DOI
- M.E. Bechler, L. Byrne, C. Ffrench-Constant, CNS myelin sheath lengths are an intrinsic property of oligodendrocytes, Curr. Biol. 25 (2015) 2411-2416, https:// doi.org/10.1016/j.cub.2015.07.056. · DOI
- G.S. Tomassy, D.R. Berger, H.-H. Chen, N. Kasthuri, K.J. Hayworth, A. Vercelli, H. S. Seung, J.W. Lichtman, P. Arlotta, Distinct profiles of myelin distribution along single axons of pyramidal neurons in the neocortex, Science 344 (2014) 319-324, https://doi.org/10.1126/science.1249766. · DOI · Paper page
- R.A. Hill, A.M. Li, J. Grutzendler, Lifelong cortical myelin plasticity and age-related degeneration in the live mammalian brain, Nat. Neurosci. 26 (2018), R971, https://doi.org/10.1038/s41593-018-0120-6. · DOI · Paper page
- F. Auer, S. Vagionitis, T. Czopka, Evidence for myelin sheath remodeling in the cns revealed by in vivo imaging, Curr. Biol. 28 (2018) 549-559, https://doi.org/ 10.1016/j.cub.2018.01.017, e3. · DOI
- Snaidero, N., Schifferer, M., Mezydlo, A., Kerschensteiner, M., Misgeld, T., n.d. Precision in a sea of profusion: myelin replacement triggered by single-cell cortical demyelination, https://doi.org/10.1101/2019.12.16.877597. · DOI
- S. Koudelka, M.G. Voas, R.G. Almeida, M. Baraban, J. Soetaert, M.P. Meyer, W. Talbot, D. Lyons, Individual neuronal subtypes exhibit diversity in cns myelination mediated by synaptic vesicle release, Curr. Biol. 26 (2016) 1447-1455, https://doi.org/10.1016/j.cub.2016.03.070. · DOI
- M.S. Windrem, S.J. Schanz, C. Morrow, J. Munir, D. Chandler-Militello, S. Wang, S. A. Goldman, A competitive advantage by neonatally engrafted human glial progenitors yields mice whose brains are chimeric for human glia, J. Neurosci. 34 (2014) 16153-16161, https://doi.org/10.1523/JNEUROSCI.1510-14.2014. · DOI
- M.S. Windrem, S.J. Schanz, L. Zou, D. Chandler-Militello, N.J. Kuypers, M. Nedergaard, Y. Lu, J.N. Mariani, S.A. Goldman, Human glial progenitor cells effectively remyelinate the demyelinated adult brain, Cell Rep. 31 (2020), 107658, https://doi.org/10.1016/j.celrep.2020.107658. · DOI
- A. Boyd, H. Zhang, A. Williams, Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models, Acta Neuropathol. 125 (2013) 841-859, https://doi.org/10.1007/s00401-013-1112-y. · DOI
- G. Piaton, M.-S. Aigrot, A. Williams, S. Moyon, V. Tepavcevic, I. Moutkine, J. Gras, K.S. Matho, A. Schmitt, H. Soellner, A.B. Huber, P. Ravassard, C. Lubetzki, Class 3 semaphorins influence oligodendrocyte precursor recruitment and remyelination in adult central nervous system, Brain 134 (2011) 1156-1167, https://doi.org/ 10.1093/brain/awr022. · DOI
- M. Segel, B. Neumann, M.F.E. Hill, I.P. Weber, C. Viscomi, C. Zhao, A. Young, C. C. Agley, A.J. Thompson, G.A. Gonzalez, A. Sharma, S. Holmqvist, D.H. Rowitch, K. Franze, R. Franklin, K.J. Chalut, Niche stiffness underlies the ageing of central nervous system progenitor cells, Nature 350 (2019), 1199-5, https://doi.org/ 10.1038/s41586-019-1484-9. · DOI · Paper page
Cited by
Sorted by citations
Graves, J. S., Krysko, K. M., Hua, L. H., Absinta, M., Franklin, R. J. M., & Segal, B. M. (2023) · The Lancet Neurology · doi:10.1016/s1474-4422(22)00184-3 · Cited by 260 · see citing works
Self-citationMicroglia promote remyelination independent of their role in clearing myelin debris
Baaklini, C. S., Ho, M. F. S., Lange, T., Hammond, B. P., Panda, S. P., Zirngibl, M., Zia, S., Himmelsbach, K., Rana, H., Phillips, B., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113574 · Cited by 73 · see citing works
Mok, K. K., Yeung, S. H., Cheng, G. W., Ma, I. W., Lee, R. H., Herrup, K., & Tse, K. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15748 · Cited by 37 · see citing works
BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis
Bergner, C. G., van der Meer, F., Franz, J., Vakrakou, A., Würfel, T., Nessler, S., Schäfer, L., Nau-Gietz, C., Winkler, A., Lagumersindez-Denis, N., et al. (2025) · Brain · doi:10.1093/brain/awae293 · Cited by 16 · see citing works
“44,45 Previous studies in human post-mortem tissue and experimental models suggested that remyelination after a demyelinating insult is more efficient in the cerebral cortex compared to the white matter.”
Neural Stem Cell‐Derived Extracellular Vesicles for Advanced Neural Repair
Moretti, E. H., Lin, A. L. Y., Peruzzotti‐Jametti, L., Pluchino, S., & Mozafari, S. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70170 · Cited by 16 · see citing works
- Authors
- Franklin, R. J. M., Frisén, J., & Lyons, D. A.
- Affiliations
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Karolinska Institutet (SE)
- University of Edinburgh (GB)
- Corresponding author
- Franklin, Robin J.M.
- Frisén, Jonas
- Lyons, David A.
- Venue
- Seminars in Cell & Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2021-08
- Volume
- 116
- Pages
- 3-9
- ISSN
- 1084-9521 (ISSN-L)
- OpenAlex
- W3093239695
- Cited by
- 154
- References
- 11
- Citations by year
- 2026: 15 · 2025: 27 · 2024: 27 · 2023: 31 · 2022: 30 · 2021: 24
- FWCI
- 3.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Seminars in Cell and Developmental Biology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Apollo
- Funders
- Sarah Neely, University
- Multiple Sclerosis Society (MS50)
- Adelson Medical Research Foundation
- Wellcome-Medical Research Council Cambridge Stem Cell Institute (203151/Z/16/Z)
- Swedish Research Council
- Swedish Cancer Society
- Strategic Research, Knut och Alice Wallenbergs Stiftelse
- ERC
- Lyons lab by the Wellcome Trust (214244/Z/18/Z)
- MRC (MR/P006272/1)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- remyelination, oligodendrocytes, oligodendrocyte precursor cells, demyelinating disease, multiple sclerosis, myelin sheath regeneration, regenerative therapy
- MeSH terms
- Remyelination, Animals, Central Nervous System, Humans, Myelin Sheath, Consensus
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
