Promotion of central nervous system remyelination by induced differentiation of oligodendrocyte precursor cells

• Published in: Annals of neurology Vol. 65; no. 3; pp. 304 - 315
• Main Authors: Mi, Sha, Miller, Robert H., Tang, Wei, Lee, Xinhua, Hu, Bing, Wu, Wutain, Zhang, Yiping, Shields, Christopher B., Zhang, Yongjie, Miklasz, Steven, Shea, Diana, Mason, Jeff, Franklin, Robin J. M., Ji, Benxiu, Shao, Zhaohui, Chédotal, Alain, Bernard, Frederic, Roulois, Aude, Xu, Janfeng, Jung, Vincent, Pepinsky, Blake
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.03.2009; Wiley-Liss
• Subjects: Animals; Animals, Newborn; Antibodies - pharmacology; Antibodies - therapeutic use; Biological and medical sciences; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cells, Cultured; Cuprizone - toxicity; Demyelinating Autoimmune Diseases, CNS - chemically induced; Demyelinating Autoimmune Diseases, CNS - drug therapy; Demyelinating Autoimmune Diseases, CNS - pathology; Demyelinating Autoimmune Diseases, CNS - physiopathology; Development. Senescence. Regeneration. Transplantation; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Ganglia, Spinal - cytology; Lysophosphatidylcholines - toxicity; Medical sciences; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - immunology; Membrane Proteins - physiology; Mice; Myelin Proteins - metabolism; Myelin Sheath - drug effects; Myelin Sheath - physiology; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - immunology; Nerve Tissue Proteins - physiology; Neurology; Oligodendroglia - physiology; Organ Culture Techniques; Rats; Rats, Sprague-Dawley; Stem Cells - drug effects; Stem Cells - physiology; Vertebrates: nervous system and sense organs; Nervous system diseases; Oligodendrocyte; Cell differentiation; Precursor; Neuroglia; Central nervous system
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.21581

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