Promotion of central nervous system remyelination by induced differentiation of oligodendrocyte precursor cells†
Corresponding Author
Sha Mi PhD
Biogen Idec, Cambridge, MA
S.M. and R.H.M. contributed equally to this work.
Department of Discovery Neurobiology, Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142Search for more papers by this authorRobert H. Miller PhD
Center for Translational Neuroscience, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH
S.M. and R.H.M. contributed equally to this work.
Search for more papers by this authorBing Hu PhD
University of Hong Kong, Pokfulam, Hong Kong SAR, China
Search for more papers by this authorWutain Wu PhD
University of Hong Kong, Pokfulam, Hong Kong SAR, China
Search for more papers by this authorYiping Zhang MD
Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, KY
Search for more papers by this authorChristopher B. Shields MD
Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, KY
Search for more papers by this authorYongjie Zhang PhD
Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, KY
Search for more papers by this authorJeff Mason PhD
Department of Molecular and Cellular Biochemistry, University of Thomas Jefferson, Philadelphia, PA
Search for more papers by this authorRobin J. M. Franklin PhD
Department of Veterinary Medicine, Cambridge Center for Brain Repair, University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorAlain Chédotal PhD
Centre National de la Recherche Scientifique 7102, Université Paris 6, Paris, France
Search for more papers by this authorFrederic Bernard PhD
Centre National de la Recherche Scientifique 7102, Université Paris 6, Paris, France
Search for more papers by this authorAude Roulois PhD
Department of Veterinary Medicine, Cambridge Center for Brain Repair, University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorCorresponding Author
Sha Mi PhD
Biogen Idec, Cambridge, MA
S.M. and R.H.M. contributed equally to this work.
Department of Discovery Neurobiology, Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142Search for more papers by this authorRobert H. Miller PhD
Center for Translational Neuroscience, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH
S.M. and R.H.M. contributed equally to this work.
Search for more papers by this authorBing Hu PhD
University of Hong Kong, Pokfulam, Hong Kong SAR, China
Search for more papers by this authorWutain Wu PhD
University of Hong Kong, Pokfulam, Hong Kong SAR, China
Search for more papers by this authorYiping Zhang MD
Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, KY
Search for more papers by this authorChristopher B. Shields MD
Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, KY
Search for more papers by this authorYongjie Zhang PhD
Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, KY
Search for more papers by this authorJeff Mason PhD
Department of Molecular and Cellular Biochemistry, University of Thomas Jefferson, Philadelphia, PA
Search for more papers by this authorRobin J. M. Franklin PhD
Department of Veterinary Medicine, Cambridge Center for Brain Repair, University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorAlain Chédotal PhD
Centre National de la Recherche Scientifique 7102, Université Paris 6, Paris, France
Search for more papers by this authorFrederic Bernard PhD
Centre National de la Recherche Scientifique 7102, Université Paris 6, Paris, France
Search for more papers by this authorAude Roulois PhD
Department of Veterinary Medicine, Cambridge Center for Brain Repair, University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorPotential conflict of interest: Nothing to report.
Abstract
Objective
Repair of demyelinated axons in diseases such as multiple sclerosis requires activation of the myelination program in existing or newly recruited oligodendrocyte precursor cells (OPCs). The control of OPC differentiation and initiation of myelination during repair is poorly understood. In this study, we test the ability of anti–LINGO-1 reagents to promote myelination in vitro and remyelination in the rodent adult central nervous system in vivo.
Methods
The effects of LINGO-1 antagonists on the differentiation of OPCs and the promotion of myelination has been assayed using a combination of coculture and slice culture preparations. Using three different animal models of demyelination and remyelination, we morphologically and functionally assessed the effects of LINGO-1 antagonists on OPC differentiation and myelin repair.
Results
The data indicate that in vitro treatment with antagonists of LINGO-1 promote OPC differentiation and myelination, whereas in vivo remyelination is accelerated in lysophosphatidylcholine- or cuprizone-induced demyelination. This remyelination is associated with enhanced OPC differentiation and functional recovery of conduction velocities in demyelinated axons.
Interpretation
Our studies demonstrate that LINGO-1 antagonism promotes OPC differentiation and remyelination, and suggest LINGO-1 functions as an inhibitor of OPC differentiation to retard central nervous system remyelination. Ann Neurol 2009;65:304–315
Supporting Information
Additional Supporting Information may be found in the online version of this article.
| Filename | Description |
|---|---|
| ANA_21581_sm_SupFig1.tif23.2 MB | Supplementary Figure 1 |
| ANA_21581_sm_SupFig2.tif23.9 MB | Supplementary Figure 2 |
| ANA_21581_sm_SupFig3.tif23 MB | Supplementary Figure 3 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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