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Cited by 63Multiple Sclerosis Research StudiesNeurogenesis and neuroplasticity mechanismsNeuroinflammation and Neurodegeneration Mechanisms

Remyelination by surviving oligodendrocytes is inefficient in the inflamed mammalian cortex

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Mezydlo, Aleksandra, Treiber, Nils, Ullrich Gavilanes, Emily Melisa, Eichenseer, Katharina, Ancău, Mihai, Wens, Adinda, Ares Carral, Carla, Schifferer, Martina +3 more·2023·Neuron
DOI 10.1016/j.neuron.2023.03.031
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Abstract

In multiple sclerosis, an inflammatory attack results in myelin loss, which can be partially reversed by remyelination. Recent studies suggest that mature oligodendrocytes could contribute to remyelination by generating new myelin. Here, we show that in a mouse model of cortical multiple sclerosis pathology, surviving oligodendrocytes can indeed extend new proximal processes but rarely generate new myelin internodes. Furthermore, drugs that boost myelin recovery by targeting oligodendrocyte precursor cells did not enhance this alternate mode of myelin regeneration. These data indicate that the contribution of surviving oligodendrocytes to myelin recovery in the inflamed mammalian CNS is minor and inhibited by distinct remyelination brakes.

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Research works printed but not linked: 43

  1. Lubetzki, C., Zalc, B., Williams, A., Stadelmann, C., and Stankoff, B. (2020). Remyelination in multiple sclerosis: from basic science to clinical translation. Lancet Neurol. 19, 678-688. https://doi.org/10.1016/S1474- 4422(20)30140-X. · DOI · Paper page
  2. Plemel, J.R., Liu, W.Q., and Yong, V.W. (2017). Remyelination therapies: a new direction and challenge in multiple sclerosis. Nat. Rev. Drug Discov. 16, 617-634. https://doi.org/10.1038/nrd.2017.115. · DOI
  3. de Faria, O., Jr., Pivonkova, H., Varga, B., Timmler, S., Evans, K.A., and Ka ´rado ´ttir, R.T. (2021). Periods of synchronized myelin changes shape brain function and plasticity. Nat. Neurosci. 24, 1508-1521. https://doi. org/10.1038/s41593-021-00917-2. · DOI
  4. Duncan, I.D., Radcliff, A.B., Heidari, M., Kidd, G., August, B.K., and Wierenga, L.A. (2018). The adult oligodendrocyte can participate in remye- lination. Proc. Natl. Acad. Sci. USA 115, E11807-E11816. https://doi.org/ 10.1073/pnas.1808064115. · DOI · Paper page
  5. J€ akel, S., Agirre, E., Mendanha Falca ˜o, A., van Bruggen, D., Lee, K.W., Knuesel, I., Malhotra, D., Ffrench-Constant, C., Williams, A., and Castelo-Branco, G. (2019). Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature 566, 543-547. https://doi.org/10.1038/ s41586-019-0903-2. · DOI · Paper page
  6. Bacmeister, C.M., Barr, H.J., McClain, C.R., Thornton, M.A., Nettles, D., Welle, C.G., and Hughes, E.G. (2020). Motor learning promotes remyelina- tion via new and surviving oligodendrocytes. Nat. Neurosci. 23, 819-831. https://doi.org/10.1038/s41593-020-0637-3. · DOI
  7. Franklin, R.J.M., Frise ´n, J., and Lyons, D.A. (2021). Revisiting remyelina- tion: towards a consensus on the regeneration of CNS myelin. Semin. Cell Dev. Biol. 116, 3-9. https://doi.org/10.1016/j.semcdb.2020.09.009. · DOI · Paper page
  8. Romanelli, E., Merkler, D., Mezydlo, A., Weil, M.T., Weber, M.S., Niki c, I., Potz, S., Meinl, E., Matznick, F.E., Kreutzfeldt, M., et al. (2016). Myelinosome formation represents an early stage of oligodendrocyte damage in multiple sclerosis and its animal model. Nat. Commun. 7, 13275. https://doi.org/10.1038/ncomms13275. · DOI
  9. Neely, S.A., Williamson, J.M., Klingseisen, A., Zoupi, L., Early, J.J., Williams, A., and Lyons, D.A. (2022). New oligodendrocytes exhibit more abundant and accurate myelin regeneration than those that survive demy- elination. Nat. Neurosci. 25, 415-420. https://doi.org/10.1038/s41593- 021-01009-x. · DOI · Paper page
  10. Neumann, B., Foerster, S., Zhao, C., Bodini, B., Reich, D.S., Bergles, D.E., Ka ´rado ´ttir, R.T., Lubetzki, C., Lairson, L.L., Zalc, B., et al. (2020). Problems and pitfalls of identifying remyelination in multiple sclerosis. Cell Stem Cell 26, 617-619. https://doi.org/10.1016/j.stem.2020.03.017. · DOI
  11. Jafari, M., Schumacher, A.M., Snaidero, N., Ullrich Gavilanes, E.M., Neziraj, T., Kocsis-Jutka, V., Engels, D., J€ urgens, T., Wagner, I., Weidinger, J.D.F., et al. (2021). Phagocyte-mediated synapse removal in cortical neuroinflam- mation is promoted by local calcium accumulation. Nat. Neurosci. 24, 355-367. https://doi.org/10.1038/s41593-020-00780-7. · DOI
  12. Bodini, B., Veronese, M., Garcı ´a-Lorenzo, D., Battaglini, M., Poirion, E., Chardain, A., Freeman, L., Louapre, C., Tchikviladze, M., Papeix, C., et al. (2016). Dynamic imaging of individual remyelination profiles in multiple scle- rosis. Ann. Neurol. 79, 726-738. https://doi.org/10.1002/ana.24620. · DOI
  13. Hughes, E.G., Orthmann-Murphy, J.L., Langseth, A.J., and Bergles, D.E. (2018). Myelin remodeling through experience-dependent oligodendro- genesis in the adult somatosensory cortex. Nat. Neurosci. 21, 696-706. https://doi.org/10.1038/s41593-018-0121-5. · DOI · Paper page
  14. Hill, R.A., Li, A.M., and Grutzendler, J. (2018). Lifelong cortical myelin plas- ticity and age-related degeneration in the live mammalian brain. Nat. Neurosci. 21, 683-695. https://doi.org/10.1038/s41593-018-0120-6. · DOI · Paper page
  15. Mei, F., Lehmann-Horn, K., Shen, Y.A., Rankin, K.A., Stebbins, K.J., Lorrain, D.S., Pekarek, K., A Sagan, S., Xiao, L., Teuscher, C., et al. (2016). Accelerated remyelination during inflammatory demyelination pre- vents axonal loss and improves functional recovery. eLife 5. https://doi. org/10.7554/eLife.18246. · DOI
  16. Neumann, B., Baror, R., Zhao, C., Segel, M., Dietmann, S., Rawji, K.S., Foerster, S., McClain, C.R., Chalut, K., van Wijngaarden, P., and Franklin, R.J.M. (2019). Metformin restores CNS remyelination capacity by rejuvenating aged stem cells. Cell Stem Cell 25. 473-485.e8. https:// doi.org/10.1016/j.stem.2019.08.015. · DOI · Paper page
  17. Mallon, B.S., Shick, H.E., Kidd, G.J., and Macklin, W.B. (2002). Proteolipid promoter activity distinguishes two populations of NG2-positive cells throughout neonatal cortical development. J. Neurosci. 22, 876-885. https://doi.org/10.1523/JNEUROSCI.22-03-00876.2002. · DOI
  18. Bø, L., Vedeler, C.A., Nyland, H.I., Trapp, B.D., and Mørk, S.J. (2003). Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J. Neuropathol. Exp. Neurol. 62, 723-732. https://doi.org/10.1093/jnen/ 62.7.723. · DOI · Paper page
  19. Hughes, E.G., Kang, S.H., Fukaya, M., and Bergles, D.E. (2013). Oligodendrocyte progenitors balance growth with self-repulsion to achieve homeostasis in the adult brain. Nat. Neurosci. 16, 668-676. https://doi.org/10.1038/nn.3390. · DOI · Paper page
  20. Huang, W., Zhao, N., Bai, X., Karram, K., Trotter, J., Goebbels, S., Scheller, A., and Kirchhoff, F. (2014). Novel NG2-CreERT2 knock-in mice demonstrate heterogeneous differentiation potential of NG2 glia dur- ing development. Glia 62, 896-913. https://doi.org/10.1002/glia.22648. · DOI
  21. Nakamura, T., Colbert, M.C., and Robbins, J. (2006). Neural crest cells retain multipotential characteristics in the developing valves and label the cardiac conduction system. Circ. Res. 98, 1547-1554. https://doi. org/10.1161/01.RES.0000227505.19472.69. · DOI
  22. Schain, A.J., Hill, R.A., and Grutzendler, J. (2014). Label-free in vivo imag- ing of myelinated axons in health and disease with spectral confocal reflectance microscopy. Nat. Med. 20, 443-449. https://doi.org/10.1038/ nm.3495. · DOI
  23. Bottes, S., and Jessberger, S. (2021). Live imaging of remyelination in the adult mouse corpus callosum. Proc. Natl. Acad. Sci. USA 118. https://doi. org/10.1073/pnas.2025795118. · DOI
  24. Muzumdar, M.D., Tasic, B., Miyamichi, K., Li, L., and Luo, L. (2007). A global double-fluorescent Cre reporter mouse. Genesis 45, 593-605. https://doi.org/10.1002/dvg.20335. · DOI · Paper page
  25. Takai, Y., Misu, T., Kaneko, K., Chihara, N., Narikawa, K., Tsuchida, S., Nishida, H., Komori, T., Seki, M., Komatsu, T., et al. (2020). Myelin oligo- dendrocyte glycoprotein antibody-associated disease: an immunopatho- logical study. Brain 143, 1431-1446. https://doi.org/10.1093/brain/ awaa102. · DOI
  26. Wang, J., He, X., Meng, H., Li, Y., Dmitriev, P., Tian, F., Page, J.C., Lu, Q.R., and He, Z. (2020). Robust myelination of regenerated axons induced by combined manipulations of GPR17 and microglia. Neuron 108. 876- 886.e4. https://doi.org/10.1016/j.neuron.2020.09.016. · DOI
  27. Keirstead, H.S., and Blakemore, W.F. (1997). Identification of post-mitotic oligodendrocytes incapable of remyelination within the demyelinated adult spinal cord. J. Neuropathol. Exp. Neurol. 56, 1191-1201. https://doi.org/ 10.1097/00005072-199711000-00003. · DOI
  28. Vigano `, F., Mo ¨bius, W., Go ¨tz, M., and Dimou, L. (2013). Transplantation re- veals regional differences in oligodendrocyte differentiation in the adult brain. Nat. Neurosci. 16, 1370-1372. https://doi.org/10.1038/nn.3503. · DOI
  29. Merkler, D., Ernsting, T., Kerschensteiner, M., Br€ uck, W., and Stadelmann, C. (2006). A new focal EAE model of cortical demyelination: multiple scle- rosis-like lesions with rapid resolution of inflammation and extensive re- myelination. Brain 129, 1972-1983. https://doi.org/10.1093/brain/awl135. · DOI · Paper page
  30. Gardner, C., Magliozzi, R., Durrenberger, P.F., Howell, O.W., Rundle, J., and Reynolds, R. (2013). Cortical grey matter demyelination can be induced by elevated pro-inflammatory cytokines in the subarachnoid space of MOG-immunized rats. Brain 136, 3596-3608. https://doi.org/ 10.1093/brain/awt279. · DOI
  31. Wolswijk, G. (2000). Oligodendrocyte survival, loss and birth in lesions of chronic-stage multiple sclerosis. Brain 123, 105-115. https://doi.org/10. 1093/brain/123.1.105. · DOI
  32. Albert, M., Antel, J., Br€ uck, W., and Stadelmann, C. (2007). Extensive cortical remyelination in patients with chronic multiple sclerosis. Brain Pathol. 17, 129-138. https://doi.org/10.1111/j.1750-3639.2006.00043.x. · DOI · Paper page
  33. Marisca, R., Hoche, T., Agirre, E., Hoodless, L.J., Barkey, W., Auer, F., Castelo-Branco, G., and Czopka, T. (2020). Functionally distinct sub- groups of oligodendrocyte precursor cells integrate neural activity and execute myelin formation. Nat. Neurosci. 23, 363-374. https://doi.org/ 10.1038/s41593-019-0581-2. · DOI
  34. Call, C.L., and Bergles, D.E. (2021). Cortical neurons exhibit diverse mye- lination patterns that scale between mouse brain regions and regenerate after demyelination. Nat. Commun. 12, 4767. https://doi.org/10.1038/ s41467-021-25035-2. · DOI
  35. Bei, F., Lee, H.H.C., Liu, X., Gunner, G., Jin, H., Ma, L., Wang, C., Hou, L., Hensch, T.K., Frank, E., et al. (2016). Restoration of visual function by enhancing conduction in regenerated axons. Cell 164, 219-232. https:// doi.org/10.1016/j.cell.2015.11.036. · DOI
  36. Barker, R.A., Go ¨tz, M., and Parmar, M. (2018). New approaches for brain repair-from rescue to reprogramming. Nature 557, 329-334. https://doi. org/10.1038/s41586-018-0087-1. · DOI · Paper page
  37. Kay, J.N., Roeser, T., Mumm, J.S., Godinho, L., Mrejeru, A., Wong, R.O., and Baier, H. (2004). Transient requirement for ganglion cells during as- sembly of retinal synaptic layers. Development 131, 1331-1342. https:// doi.org/10.1242/dev.01040. · DOI
  38. Linnington, C., Webb, M., and Woodhams, P.L. (1984). A novel myelin- associated glycoprotein defined by a mouse monoclonal antibody. J. Neuroimmunol. 6, 387-396. https://doi.org/10.1016/0165-5728(84) 90064-x. · DOI
  39. Zolotukhin, S., Byrne, B.J., Mason, E., Zolotukhin, I., Potter, M., Chesnut, K., Summerford, C., Samulski, R.J., and Muzyczka, N. (1999). Recombinant adeno-associated virus purification using novel methods improves infectious titer and yield. Gene Ther. 6, 973-985. https://doi. org/10.1038/sj.gt.3300938. · DOI
  40. Holtmaat, A., Bonhoeffer, T., Chow, D.K., Chuckowree, J., De Paola, V., Hofer, S.B., H€ ubener, M., Keck, T., Knott, G., Lee, W.C., et al. (2009). Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window. Nat. Protoc. 4, 1128-1144. https://doi.org/10. 1038/nprot.2009.89. · DOI
  41. Bishop, D., Niki c, I., Brinkoetter, M., Knecht, S., Potz, S., Kerschensteiner, M., and Misgeld, T. (2011). Near-infrared branding efficiently correlates light and electron microscopy. Nat. Methods 8, 568-570. https://doi.org/ 10.1038/nmeth.1622. · DOI
  42. Longair, M.H., Baker, D.A., and Armstrong, J.D. (2011). Simple neurite tracer: open source software for reconstruction, visualization and analysis of neuronal processes. Bioinformatics 27, 2453-2454. https://doi.org/10. 1093/bioinformatics/btr390. · DOI
  43. Tripathi, R.B., Jackiewicz, M., McKenzie, I.A., Kougioumtzidou, E., Grist, M., and Richardson, W.D. (2017). Remarkable stability of myelinating oli- godendrocytes in mice. Cell Rep. 21, 316-323. https://doi.org/10.1016/j. celrep.2017.09.050. · DOI

Cited by

Sorted by citations

Authors
Mezydlo, A., Treiber, N., Ullrich Gavilanes, E. M., Eichenseer, K., Ancău, M., Wens, A., Ares Carral, C., Schifferer, M., Snaidero, N., Misgeld, T., & Kerschensteiner, M.
Affiliations
  • LMU Klinikum (DE)
  • Hertie Institute for Clinical Brain Research (DE)
  • TUM Klinikum (DE)
  • German Center for Neurodegenerative Diseases (DE)
  • Munich Cluster for Systems Neurology (DE)
Corresponding author
  • Misgeld, Thomas
  • Kerschensteiner, Martin
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2023-06
Volume
111
Issue
11
Pages
1748-1759.e8
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2023.03.031
OpenAlex
W4366086425
Cited by
63
References
7
Citations by year
2026: 17 · 2025: 17 · 2024: 22 · 2023: 7
FWCI
11.91
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • DZNE Pub (submittedVersion)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion)
Funders
  • European Commission (2007–2013, FP/2007/2013)
  • Deutsche Forschungsgemeinschaft (518284373, 426715780, TRR- 152, TRR274/1 2020, EXC 2145, CRC 870, 24184143, FP/2007-2013, TRR-274, 774/5‐1, 428663564, 390857198, TRR128, 323061152, Mi694/7‐1, GSC 82, 408885537, 118803580, Mi 694/8-1)
  • Bundesministerium für Bildung und Forschung
  • Deutsches Zentrum für Neurodegenerative Erkrankungen
  • Universität des Saarlandes
  • Ludwig-Maximilians-Universität München
  • University of Colorado Denver
  • Graduate School of Systemic Neurosciences (ID 24184143, GSC 82)
  • FP7 Ideas: European Research Council (616791, 310932)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
remyelination, oligodendrocytes, multiple sclerosis, cortical inflammation, oligodendrocyte precursor cells, demyelination
MeSH terms
Remyelination, Animals, Axons, Mammals, Multiple Sclerosis, Myelin Sheath, Oligodendroglia, Mice

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