Multisite Injections of Canine Glial-Restricted Progenitors Promote Brain Myelination and Extend the Survival of Dysmyelinated Mice

Abstract

Glial cell dysfunction results in myelin loss and leads to subsequent motor and cognitive deficits throughout the demyelinating disease course.Therefore, in various therapeutic approaches, significant attention has been directed toward glial-restricted progenitor (GRP) transplantation for myelin repair and remyelination, and numerous studies using exogenous GRP injection in rodent models of hypomyelinating diseases have been performed. Previously, we proposed the transplantation of canine glial-restricted progenitors (cGRPs) into the double-mutant immunodeficient, demyelinated neonatal shiverer mice (shiverer/Rag2−/−). The results of our previous study revealed the myelination of axons within the corpus callosum of transplanted animals; however, the extent of myelination and lifespan prolongation depended on the transplantation site (anterior vs. posterior). The goal of our present study was to optimize the therapeutic effect of cGRP transplantation by using a multisite injection protocol to achieve a broader dispersal of donor cells in the host and obtain better therapeutic results. Experimental analysis of cGRP graft recipients revealed a marked elevation in myelin basic protein (MBP) expression and prominent axonal myelination across the brains of shiverer mice. Interestingly, the proportion of galactosyl ceramidase (GalC) positive cells was similar between the brains of cGRP recipients and control mice, implying a natural propensity of exogenous cGRPs to generate mature, myelinating oligodendrocytes. Moreover, multisite injection of cGRPs improved mice survival as compared to non-transplanted animals.