Myelination of congenitally dysmyelinated spinal cord axons by adult neural precursor cells results in formation of nodes of Ranvier and improved axonal conduction.
Emerging evidence suggests that cell-based remyelination strategies may be a feasible therapeutic approach for CNS diseases characterized by myelin deficiency as a result of trauma, congenital anomalies, or diseases. Although experimental demyelination models targeted at the transient elimination of oligodendrocytes have suggested that transplantation-based remyelination can partially restore axonal molecular structure and function, it is not clear whether such therapeutic approaches can be used to achieve functional remyelination in models associated with long-term, irreversible myelin deficiency. In this study, we transplanted adult neural precursor cells (aNPCs) from the brain of adult transgenic mice into the spinal cords of adult Shiverer (shi/shi) mice, which lack compact CNS myelin. Six weeks after transplantation, the transplanted aNPCs expressed oligodendrocyte markers, including MBP, migrated extensively along the white matter tracts of the spinal cord, and formed compact myelin. Conventional and three-dimensional confocal and electron microscopy revealed axonal ensheathment, establishment of paranodal junctional complexes leading to de novo formation of nodes of Ranvier, and partial reconstruction of the juxtaparanodal and paranodal molecular regions of axons based on Kv1.2 and Caspr (contactin-associated protein) expression by the transplanted aNPCs. Electrophysiological recordings revealed improved axonal conduction along the transplanted segments of spinal cords. We conclude that myelination of congenitally dysmyelinated adult CNS axons by grafted aNPCs results in the formation of compact myelin, reconstruction of nodes of Ranvier, and enhanced axonal conduction. These data suggest the therapeutic potential of aNPCs to promote functionally significant myelination in CNS disorders characterized by longstanding myelin deficiency.
Eftekharpour
Eftekhar
E
Division of Cell and Molecular Biology, Toronto Western Research Institute, Krembil Neuroscience Center, Toronto, Ontario, Canada M5T 2S8.
Karimi-Abdolrezaee
Soheila
S
Wang
Jian
J
El Beheiry
Hossam
H
Morshead
Cindi
C
Fehlings
Michael G
MG
D000818:Animals; D001369:Axons / Q000502:physiology / Q000648:ultrastructure; D002454:Cell Differentiation; D003711:Demyelinating Diseases / Q000151:congenital / Q000503:physiopathology* / Q000601:surgery*; D004195:Disease Models, Animal; D005071:Evoked Potentials; D051379:Mice; D008817:Mice, Mutant Strains; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000502:physiology; D009431:Neural Conduction; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000637:transplantation* / Q000648:ultrastructure; D011901:Ranvier's Nodes / Q000502:physiology* / Q000648:ultrastructure; D013118:Spinal Cord Diseases / Q000151:congenital / Q000503:physiopathology* / Q000601:surgery*; D033581:Stem Cell Transplantation
D004676:Myelin Basic Protein