Abstract
Neonatally transplanted human glial progenitor cells (hGPCs) can myelinate the brains of myelin-deficient shiverer mice, rescuing their phenotype and survival. Yet, it has been unclear whether implanted hGPCs are similarly able to remyelinate the diffusely demyelinated adult CNS. We, therefore, ask if hGPCs could remyelinate both congenitally hypomyelinated adult shiverers and normal adult mice after cuprizone demyelination. In adult shiverers, hGPCs broadly disperse and differentiate as myelinating oligodendrocytes after subcortical injection, improving both host callosal conduction and ambulation. Implanted hGPCs similarly remyelinate denuded axons after cuprizone demyelination, whether delivered before or after demyelination. RNA sequencing (RNA-seq) of hGPCs back from cuprizone-demyelinated brains reveals their transcriptional activation of oligodendrocyte differentiation programs, while distinguishing them from hGPCs not previously exposed to demyelination. These data indicate the ability of transplanted hGPCs to disperse throughout the adult CNS, to broadly myelinate regions of dysmyelination, and also to be recruited as myelinogenic oligodendrocytes later in life, upon demyelination-associated demand.
Highlights
Oligodendrocytes are the sole source of myelin in the adult CNS, and their loss or dysfunction is at the heart of a wide variety of diseases of both children and adults
Adult shiverer Mice Exhibit Myelination following human glial progenitor cells (hGPCs) Delivery To assess the ability of donor hGPCs to disperse and differentiate as oligodendroglia in the adult brain, we introduced CD140a-sorted fetal hGPCs into young adult shiverer 3 rag2À/À immune-deficient mice (Sim et al, 2011), as well as into two normally myelinated immunodeficient control lines, namely, rag1À/À on a C57BL/6 background and rag2À/À on C3H
The brains of all mice were examined for donor cell dispersal and oligodendrocytic differentiation as well as for myelin basic protein (MBP) immunoreactivity, which was necessarily donor derived in the shiverer context
Summary
Oligodendrocytes are the sole source of myelin in the adult CNS, and their loss or dysfunction is at the heart of a wide variety of diseases of both children and adults. A variety of enriched preparations of hGPCs, derived from both human brain and pluripotent stem cells, have been shown capable of remyelinating focal lesions of the adult brain and spinal cord (Buchet et al, 2011; Piao et al, 2015; Windrem et al, 2002). These latter studies were done in models of focal demyelination; it has remained unclear whether hGPCs are able to migrate extensively in adult brain tissue, as would be required for the repair of diffusely demyelinated tissue. To our knowledge, no previous study has systematically assessed the ability of hGPCs to either migrate within or remyelinate brain tissue demyelinated in adulthood
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