Glial Precursors Research
Our transplantation experiments address fundamental issues of potential and fate with respect to neural stem cells and lineage-restricted progenitors, as well as the development of therapeutic strategies for repair of spinal cord injury. We hypothesize that multipotent neural stem cells do not differentiate into neurons following transplantation because the stem cells fail to progress into lineage-restricted precursors. Our studies demonstrate that lineage-restricted precursor cells are a promising alternative to multipotential stem cells. Glial-restricted precursor (GRP) cells represent one of the most promising candidates for transplantation therapy because of their potential to remyelinate damaged or regenerating axons and produce permissive astrocytes (Wu et. al., 2002). Our studies demonstrate that grafted GRP cells not only survive and differentiate in the intact and injured spinal cord, but they also migrate long distances and may therefore provide a permissive environment at and around injury sites.
The isolation and characterization of these cells in vitro has shown that they are tripotential and can develop into astrocytes and oligodendrocytes (Wu et. al., 2002). GRP cells are committed to developing along glial lines, having lost the ability to form neurons.
However, the GRP cells' in vivo properties are not well understood with respect to survival, migration, and differentiation. We examined the fate and migration of grafted fetal GRP cells, harvested from alkaline phosphatase-expressing transgenic rats into intact and injured spinal cord. We found that transplanted GRP cells survived for at least six weeks and differentiated along astrocytic and oligodendrocytic, but not neuronal, lineages. Cells grafted into the intact spinal cord exhibitied robust migration along longitudinal white matter tracts, and, by six weeks, migrated more than fifteen millimeters.
In contrast, migration of GRP cells in the gray matter was very limited. We then examined the phenotypic properties of proliferating endogenous precursors in response to injury by BrdU labeling. The predominant proliferating population seen after injury consisted of GRP-like cells with NKx2.2/oligo2 phenotype. Incorporation of BrdU by endogenous cells suggests that the environment provides proliferation signals and is permissive to glial precursor survival. To test if exogenous GRP cells would respond similarly, we transplanted GRP cells into a lateral funiculus injury. GRP cells survived and differentiated along glial lineages and migrated along white matter tracts in the injured spinal cord. GRP cell transplants may therefore provide a cellular transplant that can respond to appropriate endogenous cues to produce therapeutic molecules and produce new glial cells after injury.
Isolation of a glial-restricted tripotential cell line from embryonic spinal cord cultures (abstract)
Wu YY, Mujtaba T, Han SSW, Fischer I and Rao MS.
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