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New oligodendrocytes exhibit more abundant and accurate myelin regeneration than those that survive demyelination

Abstract

Oligodendrocytes that survive demyelination can remyelinate, including in multiple sclerosis (MS), but how they do so is unclear. In this study, using zebrafish, we found that surviving oligodendrocytes make few new sheaths and frequently mistarget new myelin to neuronal cell bodies, a pathology we also found in MS. In contrast, oligodendrocytes generated after demyelination make abundant and correctly targeted sheaths, indicating that they likely also have a better regenerative potential in MS.

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Fig. 1: Remyelination by oligodendrocytes that survive demyelination in the Tg(mbp:TRPV1-tagRFPt) zebrafish model.
Fig. 2: Myelin sheath dynamics of surviving oligodendrocytes after demyelination in the Tg(mbp:TRPV1-tagRFPt) zebrafish model.
Fig. 3: Mistargeted myelin profiles are present in remyelinating lesions in motor cortex tissue from people with MS.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code availability

No code was used in this manuscript.

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Acknowledgements

We thank C. ffrench-Constant, E. Hughes and the Lyons Laboratory for feedback, the Bioresearch & Veterinary Services aquatics facility for fish care, S. Mitchell for electron microscopy assistance and C. Melendez-Vasquez for suggesting the ROCK experiment. This work was supported by Wellcome Trust Senior Research Fellowships (102836/Z/13/Z and 214244/Z/18/Z), a Medical Research Council Project Grant (MR/P006272/1) and an MS Society Innovative Grant (95) to D.A.L. S.A.N. and J.M.W. were supported by the Wellcome Trust Four-Year Ph.D. Program in Tissue Repair (grant 108906/Z/15/Z) and J.M.W. by a University of Edinburgh Ph.D. Tissue Repair Studentship Award (MRC Doctoral Training Partnership MR/K501293/1). L.Z. and A.W. were supported by an MS Society UK Centre grant.

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Contributions

S.A.N., J.M.W. and D.A.L. conceived the project. S.A.N., J.M.W., A.K. and J.J.E. designed and performed the in vivo experiments. L.Z. and A.W. designed and performed the human tissue experiments. S.A.N. and D.A.L. co-wrote the manuscript, edited by all. D.A.L. managed the project.

Corresponding author

Correspondence to David A. Lyons.

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The authors declare no competing interests.

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Nature Neuroscience thanks Bruce Appel, Jennifer Orthmann-Murphy, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Characterisation of the Tg(mbp:TRPV1-tagRFPt) zebrafish model.

(a) Schematic illustrating the Tg(mbp:TRPV1-tagRFPt) demyelination model made using Biorender. The rat ortholog of the TRPV1 channel is expressed in myelinating oligodendrocytes and is activated by addition of csn which drives cation influx. Zebrafish TRPV1 channels are insensitive to csn, therefore csn treatment specifically results in damage to myelinating glia which express the rat ortholog of the TRPV1 channel. (b) Confocal images of myelinating oligodendrocytes in the Tg(mbp:EGFP; mbp:TRPV1- tagRFPt) zebrafish line at 4dpf showing oligodendrocytes co-expressing EGFP and tagRFPt in the merged image. Scale bar, 20 µm. (c) Brightfield images of a zebrafish containing the Tg(mbp:TRPV1-tagRFPt) transgene (TRPV1 + ve), or wildtype siblings without the Tg(mbp:TRPV1-tagRFPt) transgene (TRPV1-ve) which show no developmental differences at 4dpf. Scale bars, 500 µm. (d and e) Confocal images of the (d) Tg(mbp:EGFP-CAAX) line and (e) the Tg(mbp:EGFP) line pre-treatment (indicated here as pre-t) at 4dpf, and 3hpt. Zebrafish not containing the Tg(mbp:TRPV1-tagRFPt) transgene show no disruption to myelin or oligodendrocytes following a 2 hour treatment of 10 µM csn. Scale bars, 20 µm. (f) Confocal images of myelin visualised in Tg(mbp:EGFP-CAAX; mbp:TRPV1-tagRFPt) zebrafish, with control (DMSO) and csn treated animals in top and bottom panels respectively pre-treatment (pre-t) at 4dpf, 3hpt, 1dpt and 3dpt. Scale bar, 20 µm.

Extended Data Fig. 2 Csn treatment induces severe demyelination in the Tg(mbp:TRPV1-tagRFPt) zebrafish model.

(a) Transmission electron microscopy images of DMSO and csn treated Tg(mbp:TRPV1-tagRFPt) zebrafish at 1dpt show numerous large calibre myelinated axons (blue) in DMSO treated animals and numerous large calibre unmyelinated axons (yellow) in csn treated animals. Scale bar, 1 µm. (b) Quantification of the number of myelinated axons>0.4 µm diameter in the dorsal spinal cord at 1dpt in DMSO (median = 20.00, IQR = 16.50-22.00) versus csn (median = 0.00, IQR = 0.00-1.50) treated zebrafish, p < 0.0001. Unpaired two-tailed t-test with Welch’s correction. N = 5 zebrafish per condition. Data are presented as median with IQR. (c) Quantification of the number of unmyelinated axons>0.4 µm diameter in the dorsal spinal cord at 1dpt in DMSO (mean = 10.00 ± 5.24 SD) versus csn (mean = 27.40 ± 9.61 SD) treated zebrafish, p = 0.0075. Unpaired two-tailed t-test. N = 5 zebrafish per condition. Data are presented as mean ± SD. (d) Quantification of the number of axons >0.4 µm diameter in the dorsal spinal cord at 1dpt in DMSO (mean = 29.40 ± 8.26 SD) versus csn (mean = 28.00 ± 9.95 SD) treated zebrafish, p = 0.8148. Unpaired two-tailed t-test. N = 5 zebrafish per condition. Data are presented as mean ± SD. (e) Quantification of the number of axons with>3 myelin wraps in the dorsal spinal cord at 1dpt in DMSO (median = 20.00, IQR = 15.00-20.00) versus csn (median = 0.00, IQR = 0.00-1.50) treated zebrafish, p = 0.0079. Two-tailed Mann-Whitney test. N = 5 zebrafish per condition. Data are presented as median with IQR (f) Quantification of the number of axons with ≤3 myelin wraps in the dorsal spinal cord at 1dpt in DMSO (median = 1.00, IQR = 0.00-3.00) versus csn (median = 0.00, IQR = 0.00-0.00) treated zebrafish, p = 0.1667. Two-tailed Kolmogorov-Smirnov test. N = 5 zebrafish per condition. Data is presented as median with IQR. (g) Transmission electron microscopy images of DMSO and csn treated Tg(mbp:TRPV1-tagRFPt) zebrafish at 3dpt show numerous large calibre myelinated axons (>3 myelin wraps highlighted in blue, ≤3 myelin wraps highlighted in orange) and unmyelinated axons (highlighted in yellow) in DMSO and csn treated animals. Scale bar, 1 µm. (h) Quantification of the number of myelinated axons >0.4 µm diameter in the dorsal spinal cord at 3dpt in DMSO (mean = 24.20 ± 9.83 SD) versus csn (mean = 20.83 ± 5.78 SD) treated zebrafish, p = 0.4963. Unpaired two-tailed t-test. N = 5 DMSO treated zebrafish, N = 6 csn treated zebrafish. Data are presented as mean ± SD. (i) Quantification of the number of unmyelinated axons>0.4 µm diameter in the dorsal spinal cord at 3dpt in DMSO (mean = 23.20 ± 6.76 SD) versus csn (mean = 30.17 ± 3.97 SD) treated zebrafish, p = 0.0616. Unpaired two-tailed t-test. N = 5 DMSO treated zebrafish, N = 6 csn treated zebrafish. Data are presented as mean ± SD. (j) Quantification of the number of axons>0.4 µm diameter in the dorsal spinal cord at 3dpt in DMSO (mean = 47.60 ± 10.92 SD) versus csn (mean = 51.00 ± 6.45 SD) treated zebrafish, p = 0.5359. Unpaired two-tailed t-test. N = 5 DMSO treated zebrafish, N = 6 csn treated zebrafish. (k) Quantification of the number of axons with>3 myelin wraps in the dorsal spinal cord at 3dpt in DMSO (median = 16.00, IQR = 15.50-27.00) versus csn (median = 8.50, IQR = 3.75-11.50) treated zebrafish, p = 0.0152. Two-tailed Mann-Whitney test. N = 5 DMSO treated zebrafish, N = 6 csn treated zebrafish. (l) Quantification of the number of axons with≤3 myelin wraps in the dorsal spinal cord at 3dpt in DMSO (mean = 4.00 ± 3.24 SD) versus csn (mean = 12.50 ± 5.01 SD) treated zebrafish, p = 0.0099. Unpaired two-tailed t-test. N = 5 DMSO treated zebrafish, N = 6 csn treated zebrafish.

Extended Data Fig. 3 Csn treatment induces minimal oligodendrocyte loss in the Tg(mbp:TRPV1-tagRFPt) model.

(a) Confocal images of myelinating oligodendrocytes visualised in Tg(mbp:EGFP; mbp:TRPV1-tagRFPt) zebrafish, with control (DMSO) and csn treated animals in top and bottom panels respectively pre-treatment (pre-t) at 4dpf, 3hpt, 1dpt and 3dpt. Scale bar, 20 µm. (b-f) Quantification of myelinating oligodendrocyte number in DMSO and csn treated Tg(mbp:EGFP; mbp:TRPV1-tagRFPt) zebrafish over time. (b) Pre-treatment DMSO (mean = 58.60 ± 13.23 SD) versus csn (mean = 57.20 ± 7.64 SD), p = 0.7753. Data are presented as mean ± SD. (c) 3hpt DMSO (mean = 65.00 ± 14.93 SD) versus csn (mean = 44.11 ± 10.36 SD), p = 0.0041. Data are presented as mean ± SD. (d) 1dpt DMSO (mean = 76.90 ± 14.14 SD) versus csn (mean = 61.70 ± 7.39 SD), p = 0.0075. Data are presented as mean ± SD. (e) 3dpt DMSO (mean = 99.00 ± 15.93 SD) versus csn (mean = 85.70 ± 11.83 SD), p = 0.0444. Data are presented as mean ± SD. (f) 5dpt DMSO (mean = 104.5 ± 12.95 SD) versus csn (mean = 108.5 ± 15.10 SD), p = 0.5328. (b-f) Unpaired two-tailed t-tests. Pre-treatment N = 10 zebrafish per treatment group, 3hpt N = 8 (DMSO) and 9 (csn) treated zebrafish, 1dpt N = 10 zebrafish per treatment group, 3dpt N = 11 zebrafish (DMSO) and 10 zebrafish (csn), 5 dpt N = 10 zebrafish per treatment group. Data are presented as mean ± SD. Each data point represents total (dorsal + ventral) oligodendrocyte number analysed per imaged area per zebrafish.

Extended Data Fig. 4 Characterisation of single oligodendrocyte loss and myelin debris phagocytosis following demyelination in the Tg(mbp:TRPV1-tagRFPt) zebrafish model.

(a) Confocal images of a single oligodendrocyte labelled with mbp:EGFP-CAAX in the Tg(mbp:TRPV1-tagRFPt) line pre-treatment (pre-t) at 4dpf, and 3hpt. An example of oligodendrocyte cell death is demonstrated here by the disappearance of a tagRFPt+ve cell body following csn treatment in the same zebrafish before and after demyelination, whilst 2 tagRFPt+ve oligodendrocytes which survive demyelination are seen neighbouring it at 3hpt. Arrows indicate the location of the oligodendrocyte cell body which undergoes cell death, or where it was prior to demyelination. Scale bar, 20 µm. (b) Confocal images of microglia / macrophage engulfment of myelin debris following demyelination at 1dpt. Arrowheads highlight the location of myelin debris engulfment. Scale bar, 20 µm. (c) Quantification of the number of mpeg+ve cells (macrophages / microglia) in a 4-somite section of the spinal cord at pre-treatment (mean = 1.38 ± 0.74 SD), 1dpt (mean = 2.14 ± 1.07 SD), 2dpt (mean = 3.14 ± 0.38 SD), 3dpt (mean = 2.57 ± 1.90 SD) and 4dpt (mean = 3.00 ± 1.29 SD) (where treatment was a DMSO control). Pre-t vs 1dpt p = 0.7196, pre-t vs 2dpt p = 0.0505, pre-t vs 3dpt p = 0.3106, pre-t vs 4dpt p = 0.0844, 1dpt vs 2dpt p = 0.5190, 1dpt vs 3dpt p = 0.9597, 1dpt vs 4dpt p = 0.6588, 2dpt vs 3dpt p = 0.8930, 2dpt vs 4dpt p = 0.9994, 3dpt vs 4dpt p = 0.9597. Ordinary one-way ANOVA with Tukey’s multiple comparison test. Pre-treatment N = 8 zebrafish, 1–4dpt N = 7 zebrafish. Data are presented as mean ± SD. (D) Quantification of the number of mpeg+ve cells (macrophages / microglia) in a 4-somite section of the spinal cord at pre-treatment (mean = 1.56 ± 1.01 SD), 1dpt (mean = 7.88 ± 2.75 SD), 2dpt (mean = 10.38 ± 3.42 SD), 3dpt (mean = 9.12 ± 2.48 SD) and 4dpt (mean = 6.63 ± 1.92 SD) (where treatment was a demyelinating csn treatment). Pre-t vs 1dpt p < 0.0001, pre-t vs 2dpt p < 0.0001, pre-t vs 3dpt p < 0.0001, pre-t vs 4dpt p = 0.0011, 1dpt vs 2dpt p = 0.2586, 1dpt vs 3dpt p = 0.8394, 1dpt vs 4dpt p = 0.8394, 2dpt vs 3dpt p = 0.8394, 2dpt vs 4dpt p = 0.0294, 3dpt vs 4dpt p = 0.2586. Ordinary one-way ANOVA with Tukey’s multiple comparison test. Pre-treatment N = 9 zebrafish, 1–4dpt N = 8 zebrafish. Data are presented as mean ± SD.

Extended Data Fig. 5 ROCK inhibitor treatment further increases myelin mistargeting by surviving oligodendrocytes in the Tg(mbp:TRPV1-tagRFPt) zebrafish model.

(a) Confocal images of single oligodendrocytes which have not undergone demyelination treated with DMSO (control) or Y27632 ROCK inhibitor and imaged at 4dpf. Scale bar, 20 µm. (b) Confocal images of single surviving oligodendrocytes followed over time from prior to demyelination (csn treatment) at 4dpf through to 3dpt. Following demyelination oligodendrocytes were treated with either DMSO (control) or Y27632 ROCK inhibitor. Scale bars, 20 µm. (c) Quantification of the number of sheaths produced in oligodendrocytes which have not been demyelinated in control (mean = 16.08 ± 5.73 SD) and Y27632 ROCK inhibitor (mean = 19.35 ± 4.08 SD) treated zebrafish, p = 0.0386. Unpaired two-tailed t-test. N = 24 oligodendrocytes from 24 zebrafish (control), N = 20 oligodendrocytes from 20 zebrafish (Y27632). Data are presented as mean ± SD. (d) Quantification of the average sheath length (µm) produced in oligodendrocytes which have not been demyelinated in control (mean = 28.62 ± 7.18 SD) and Y27632 ROCK inhibitor (mean = 27.26 ± 6.91 SD) treated zebrafish, p = 0.5308. Unpaired two-tailed t-test. N = 24 oligodendrocytes from 24 zebrafish (control), N = 20 oligodendrocytes from 20 zebrafish (Y27632). Data are presented as mean ± SD. (e) Quantification of the number of mistargeted myelin profiles produced in oligodendrocytes which have not been demyelinated in control (median = 0.00, IQR = 0.00-0.00) and Y27632 ROCK inhibitor (median = 0.00, IQR = 0.00-0.00) treated zebrafish, p > 0.9999. Two-tailed Mann-Whitney test. N = 24 oligodendrocytes from 24 zebrafish (control), N = 20 oligodendrocytes from 20 zebrafish (Y27632). Data are presented as median with IQR. (f) Quantification of the number of sheaths produced per oligodendrocyte following demyelination in control (median = 3.00, IQR=1.50-3.00) and Y27632 ROCK inhibitor (median = 4.00, IQR = 1.00-4.50) treated zebrafish, p = 0.5964. Two-tailed Mann-Whitney test. N = 5 oligodendrocytes from 5 zebrafish (control), N = 9 oligodendrocytes from 9 zebrafish (Y27632). Data are presented as median with IQR. (g) Quantification of the number of mistargeted myelin profiles produced per oligodendrocyte following demyelination in control (median = 1.00, IQR = 1.00-2.00) and Y27632 ROCK inhibitor (median = 3.00, IQR = 1.50-4.75) treated zebrafish, p = 0.0414. Unpaired two tailed t-test with Welch’s correction. N = 5 oligodendrocytes from 5 zebrafish (control), N = 8 oligodendrocytes from 8 zebrafish (Y27632). Data are presented as mean ± SD.

Extended Data Fig. 6 Mistargeted myelin profiles are present in remyelinating lesions in motor cortex tissue from people with MS.

(a) Low magnification image of chromogenic immunohistochemistry for proteolipid protein (PLP - brown) and NeuN (blue) in human MS motor cortex. Outline of quantified areas shown with lesion area highlighted in red, perilesion area highlighted in green, normal appearing grey matter (NAGM) in purple and white matter indicated by ‘WM’ in white. Images 1 and 2 show examples of quantified areas in 2 different human MS motor cortex samples. Scale bars, 2000 µm. (B and C) High magnification images of chromogenic immunohistochemistry for proteolipid protein (PLP - brown) and NeuN (blue) in human MS motor cortex. (b) Images 1-9 show example images of PLP+ve wrapped NeuN+ve cells (myelinated neuronal cell bodies). Images 1 and 3-9 scale bars, 20 µm. Image 2 scale bar, 10 µm. (c) Images 1-5 show example images of PLP + ve wrapped NeuN-ve cells (oligodendrocytes). Scale bars, 20 µm. (d) Fluorescent immunohistochemistry for NeuN (white), PLP (red) and Hoechst (nuclei-blue) in human MS motor cortex. Arrows indicate the location of PLP + ve wrapped NeuN+ve Hoechst+ve cells (myelinated neuronal cell body). Scale bar, 20 µm. (e) Images 1-5 show example images of CNPase+ve wrapped NeuN+ve cells (myelinated neuronal cell bodies). Scale bars, 20 µm. (f) Fluorescent immunohistochemistry for NeuN (green), CNPase (magenta) and Hoechst (nuclei-blue) in human MS motor cortex. Arrows indicate the location of CNPase+ve wrapped NeuN+ve Hoechst+ve cells. Scale bar, 20 µm.

Extended Data Fig. 7 Extensive remyelination by newly generated oligodendrocytes in the Tg(mbp:TRPV1-tagRFPt) zebrafish model.

(a) Confocal images of csn treated zebrafish with oligodendrocytes newly generated after demyelination. Arrows show position of oligodendrocyte cell bodies. Scale bars, 20 µm. (b) Quantification of the total myelin produced per oligodendrocyte (calculated by multiplying number of sheaths per oligodendrocyte by the average sheath length per oligodendrocyte) (mean = 521.5 ± 138.30 SD), versus the same oligodendrocytes 3dpt (mean = 47.18 ± 26.57 SD) and by newly differentiated oligodendrocytes at 3dpt (mean = 491.80 ± 199.10 SD). Pre-treatment versus surviving p < 0.0001, pre-treatment versus newly differentiated p = 0.8271, surviving versus newly differentiated p < 0.0001. Ordinary one-way ANOVA with Tukey’s multiple comparison test. N = 15 oligodendrocytes from 15 zebrafish (pre-treatment and surviving). N = 20 oligodendrocytes from 11 zebrafish (newly differentiated). Data are presented as mean ± SD.

Extended Data Fig. 8 Summary Schematic.

Summary schematic outlining the responses of oligodendrocytes which survive demyelination and those newly generated after demyelination made using Biorender.

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Neely, S.A., Williamson, J.M., Klingseisen, A. et al. New oligodendrocytes exhibit more abundant and accurate myelin regeneration than those that survive demyelination. Nat Neurosci 25, 415–420 (2022). https://doi.org/10.1038/s41593-021-01009-x

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