Schwann cells genetically engineered to express PSA show enhanced migratory potential without impairment of their myelinating ability in vitro.
Schwann cells, the myelin-forming cells of the PNS, are attractive candidates for remyelination therapy as they can remyelinate CNS axons. Yet their integration in CNS tissue appears hampered, at least in part, by their limited motility in the CNS environment. As the polysialylated (PSA) form of NCAM regulates migration of neural precursors in the CNS and is not expressed by developing Schwann cells, we investigated whether conferring sustained expression of PSA to Schwann cells derived from postnatal rats enhances their motility. Cells were transduced with a retrovirus encoding polysialyl-transferase STX, an enzyme that synthesizes PSA on NCAM. Migration of wild type and transduced cells expressing STX or the marker gene alkaline phosphatase was examined using a gap bridging assay in dissociated cells and by grafting cells in slice cultures of postnatal brain. Migration of PSA expressing cells was significantly increased in both models, as compared to control cells, and this effect was abolished by endoneuraminidase-N stripping of PSA. PSA-positive Schwann cells retained the ability to differentiate in vitro and expressed the Krox20 and P zero myelination markers. When grafted in neonatal cerebellar slices, STX-transduced cells started to myelinate Purkinje cell axons like control cells and make myelin internodes after 2 to 3 weeks. PSA was redistributed on the cell membrane and downregulated during differentiation in pure Schwann cell cultures and slice co-cultures. Thus, migratory properties of PNS myelin-forming cells within the CNS can be enhanced without altering their differentiation program. This finding may be beneficial for the development of remyelination therapies.
Lavdas
Alexandros A
AA
Laboratory of Cellular and Molecular Neurobiology, Hellenic Pasteur Institute, 127 Vas. Sofias, 11521 Athens, Greece.
Franceschini
Isabelle
I
Dubois-Dalcq
Monique
M
Matsas
Rebecca
R
D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000502:physiology / Q000648:ultrastructure; D015415:Biomarkers / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D005818:Genetic Engineering / Q000379:methods; D005822:Genetic Vectors; D018993:Myelin P0 Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism* / Q000648:ultrastructure; D009416:Nerve Regeneration / Q000502:physiology; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism*; D009924:Organ Culture Techniques; D010525:Peripheral Nerves / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D012794:Sialic Acids / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D012799:Sialyltransferases / Q000235:genetics; D014161:Transduction, Genetic / Q000379:methods; D015854:Up-Regulation / Q000502:physiology
D015415:Biomarkers; D051767:Early Growth Response Protein 2; D018993:Myelin P0 Protein; D039842:Neural Cell Adhesion Molecule L1; D012794:Sialic Acids; C021319:polysialic acid; C103469:polysialyl neural cell adhesion molecule; C046778:CMP-N-acetylneuraminate-poly-alpha-2,8-sialosyl sialyltransferase; D012799:Sialyltransferases