Abstract
Background: Dysfunction of glia contributes to the deterioration of the central nervous system in a wide array of neurological disorders, thus global replacement of glia is very attractive. Human glial-restricted precursors (hGRPs) transplanted intraventricularly into neonatal mice extensively migrated and rescued the lifespan in half of the studied mice, whereas mouse GRPs (mGRPs) presented no therapeutic benefit. We studied in the same experimental setting canine GRPs (cGRP) to determine whether their therapeutic potential falls between hGRPs and mGRPs. Additional motivation for the selection of cGRPs was a potential for use in veterinary medicine. Methods: cGRPs were extracted from the brain of dog fetuses. The cells were transplanted into the anterior or posterior aspect of the lateral ventricle (LV) of neonatal, immunodeficient, dysmyelinated mice (Mbpshi, Rag2 KO; shiv/rag2). Outcome measures included early cell biodistribution, animal survival and myelination assessed with MRI, immunohistochemistry and electron microscopy. Results: Grafting of cGRP into posterior LV significantly extended animal survival, whereas no benefit was observed after anterior LV transplantation. In contrast, myelination of the corpus callosum was more prominent in anteriorly transplanted animals. Conclusions: The extended survival of animals after transplantation of cGRPs could be explained by the vicinity of the transplant near the brain stem.
Highlights
CNS diseases are becoming a major burden to society [1,2,3]
We have recently shown in a mouse model of dysmyelination (Mbpshi; shiv, which was immunodeficient to avoid graft rejection; rag2 knockout (KO)) that a robust therapeutic effect of human glial-restricted precursors correlates well with their distribution throughout the entire mouse brain, whereas mouse GRPs characterized by limited migration, failed to provide any therapeutic effect [16]
We hypothesized there are at least two reasons for such behaviors: (1) the GRPs execute their own intrinsic developmental program (IDP), which is closely linked with the size of the brain and species-appropriate dynamics of myelination, more Human glial-restricted precursors (hGRPs) migrate far and myelinate late, and oppositely mouse GRPs (mGRPs) migrate short and myelinate early, and (2) due to a human-mouse mismatch, xenografted hGRPs cannot fully respond to the host cues driving the maturation of oligodendrocytes, allowing them to remain longer in a highly migratory undifferentiated state and extensively migrate
Summary
Glia are major components of the central nervous system [4], and contribute to a wide array of disorders including neurological [5,6] and psychiatric conditions [7,8]. We have recently shown in a mouse model of dysmyelination (Mbpshi; shiv, which was immunodeficient to avoid graft rejection; rag knockout (KO)) that a robust therapeutic effect of human glial-restricted precursors (hGRPs) correlates well with their distribution throughout the entire mouse brain, whereas mouse GRPs (mGRPs) characterized by limited migration, failed to provide any therapeutic effect [16]. Human glial-restricted precursors (hGRPs) transplanted intraventricularly into neonatal mice extensively migrated and rescued the lifespan in half of the studied mice, whereas mouse GRPs (mGRPs) presented no therapeutic benefit. Results: Grafting of cGRP into posterior LV significantly extended animal survival, whereas no benefit was observed after anterior LV transplantation. Conclusions: The extended survival of animals after transplantation of cGRPs could be explained by the vicinity of the transplant near the brain stem
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