Differential myelinogenic capacity of specific developmental stages of the oligodendrocyte lineage upon transplantation into hypomyelinating hosts

Abstract

The capacity of oligodendrocytes (OLs) and their progenitors to migrate, proliferate, and differentiate in vivo was evaluated by transplanting highly enriched populations of sequential stage of the OL lineage (A2B5⁺ O4⁻, O4⁺ GalC⁻, and GalC⁺) into the telencephalon of the hypomyelinating mouse, shiverer. The shiverer mouse neither expresses the major myelin basic protein (MBP) nor makes normal myelin due to a large deletion in the gene for MBP. Thirty days after transplantation, serial 225 μm sections of the host brain were immunostained with antiserum to MBP and analyzed by confocal microscopy. The presence of MBP⁺ patches of myelin in the otherwise MBP⁻ host brain allowed a retrospective analysis of the myelinogenic activity of the transplanted progenitors cells. Both the extent of MBP⁺ myelin and the location of MBP⁺ structures relative to the initial site of cell deposition were highly dependent on the developmental stage of the transplanted cells. Specifically, A2B5⁺ O4⁻ OL progenitors migrated distances of ≥ 600 μm and produced MBP⁺ patches in nearly every slice of the host brain. An average of over 250 separate patches were found per host brain, some of which had cross-sectional areas of > 250,000 μm² containing as many as 60 MBP⁺ OL cell bodies, and with densities of myelination rivaling that of normal brain. In marked contrast, transplantation of O4⁺ GalC⁻ cells produced only small (1,000–25,000 μm²), scattered (25–40 per brain) patches of MBP⁺ myelin containing one to five cell bodies, all of which were within 50 μm of the needle track or the nearest ventricular surface. GalC⁺ cells produced MBP⁺ myelin at a level similar to that of O4⁺ CalC⁻ cells. These data suggest that the developmental transition of OL progenitors from the O4⁻ to the O4⁺ pheno-type is accompanied by a dramatic reduction in the innate capacity of the cells to migrate and survive in vivo. The use of developmentally identified, enriched populations of OL progenitor cells offers the opportunity for more precise analyses of transplantation and remyelination behavior, and relates to clinically relevant studies indicating that contaminant cell types can seriously interfere with the stable integration of donor tissue into the host.