Ectopic expression of polysialylated neural cell adhesion molecule in adult macaque Schwann cells promotes their migration and remyelination potential in the central nervous system

• Published in: Brain (London, England : 1878) England : 1878), 2010-02, Vol.133 (2), p.406-420
• Main Authors: Bachelin, C., Zujovic, V., Buchet, D., Mallet, J., Baron-Van Evercooren, A.
• Format: Article
• Language: English
• Subjects: Age Factors; Animals; Animals, Newborn; Base Sequence; Biological and medical sciences; Cell Movement - physiology; Cells, Cultured; Central Nervous System - cytology; Central Nervous System - physiology; CNS; Development. Senescence. Regeneration. Transplantation; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Macaca; Macaca fascicularis; Medical sciences; Mice; Mice, Nude; migration; Molecular Sequence Data; Myelin Sheath - metabolism; Myelin Sheath - physiology; Nerve Fibers, Myelinated - physiology; Neural Cell Adhesion Molecule L1 - biosynthesis; Neural Cell Adhesion Molecule L1 - genetics; Neural Cell Adhesion Molecule L1 - physiology; Neurology; Original; Primates; Rats; remyelination; Schwann cells; Schwann Cells - cytology; Schwann Cells - physiology; Sialic Acids - biosynthesis; Sialic Acids - genetics; Sialic Acids - physiology; STX; Vertebrates: nervous system and sense organs
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awp256

Recent findings suggested that inducing neural cell adhesion molecule polysialylation in rodents is a promising strategy for promoting tissue repair in the injured central nervous system. Since autologous grafting of Schwann cells is one potential strategy to promote central nervous system remyelination, it is essential to show that such a strategy can be translated to adult primate Schwann cells and is of interest for myelin diseases. Adult macaque Schwann cells were transduced with a lentiviral vector encoding sialyltransferase, an enzyme responsible for neural cell adhesion molecule polysialylation. In vitro, we found that ectopic expression of polysialylate promoted adult macaque Schwann cell migration and improved their integration among astrocytes in vitro without modifying their antigenic properties as either non-myelinating or pro-myelinating. In addition, forced expression of polysialylate in adult macaque Schwann cells decreased their adhesion with sister cells. To investigate the ability of adult macaque Schwann cells to integrate and migrate in vivo, focally induced demyelination was targeted to the spinal cord dorsal funiculus of nude mice, and both control and sialyltransferase expressing Schwann cells overexpressing green fluorescein protein were grafted remotely from the lesion site. Analysis of the spatio-temporal distribution of the grafted Schwann cells performed in toto and in situ, showed that in both groups, Schwann cells migrated towards the lesion site. However, migration of sialyltransferase expressing Schwann cells was more efficient than that of control Schwann cells, leading to their accelerated recruitment by the lesion. Moreover, ectopic expression of polysialylated neural cell adhesion molecule promoted adult macaque Schwann cell interaction with reactive astrocytes when exiting the graft, and their ‘chain-like’ migration along the dorsal midline. The accelerated migration of sialyltransferase expressing Schwann cells to the lesion site enhanced their ability to compete for myelin repair with endogenous cells, while control Schwann cells were unable to do so. Finally, remyelination by the exogenous sialyltransferase expressing Schwann cells restored the normal distribution of paranodal and nodal elements on the host axons. These greater performances of sialyltransferase expressing Schwann cell correlated with their sustained expression of polysialylated neural cell adhesion molecule at early times when migrating from the graf