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1.  Transplanted Glial Restricted Precursor Cells Improve Neurobehavioral and Neuropathological Outcomes in a Mouse Model of Neonatal White Matter Injury Despite Limited Cell Survival 
Glia  2014;63(3):452-465.
Objective
Neonatal White Matter Injury (NWMI) is the leading cause of cerebral palsy and other neurocognitive deficits in prematurely-born children, and no restorative therapies exist. Our objective was to determine the fate and effect of glial restricted precursor cell (GRP) transplantation in an ischemic mouse model of NWMI.
Methods
Neonatal CD-1 mice underwent unilateral carotid artery ligation on postnatal-day 5 (P5). At P22, intracallosal injections of either eGFP+ GRPs or saline were performed in control and ligated mice. Neurobehavioral and postmortem studies were performed at four and eight weeks post-transplantation.
Results
GRP survival was comparable at one month but significantly lower at two months post-transplantation in NWMI mice compared to unligated controls. Surviving cells showed better migration capability in controls; however, the differentiation capacity of transplanted cells was similar in control and NWMI. Saline-treated NWMI mice showed significantly altered response in startle amplitude and pre-pulse inhibition paradigms compared to unligated controls, while these behavioral tests were completely normal in GRP-transplanted animals. Similarly, there was significant increase in hemispheric myelin basic protein density, along with significant decrease in pathologic axonal staining in cell-treated NWMI mice compared to saline-treated NWMI animals.
Interpretation
The Reduced long-term survival and migration of transplanted GRPs in an ischemia-induced NWMI model suggests that neonatal ischemia leads to long-lasting detrimental effects on oligodendroglia even months after the initial insult. Despite limited GRP-survival, behavioral and neuropathological outcomes were improved after GRP-transplantation. Our results suggest that exogenous GRPs improve myelination through trophic effects in addition to differentiation into mature oligodendrocytes.
doi:10.1002/glia.22764
PMCID: PMC4293328  PMID: 25377280
Cell Therapy; Cerebral Palsy; Ischemia; Myelination
2.  Derivation of Glial Restricted Precursors from E13 mice 
This is a protocol for derivation of glial restricted precursor (GRP) cells from the spinal cord of E13 mouse fetuses. These cells are early precursors within the oligodendrocytic cell lineage. Recently, these cells have been studied as potential source for restorative therapies in white matter diseases. Periventricular leukomalacia (PVL) is the leading cause of non-genetic white matter disease in childhood and affects up to 50% of extremely premature infants. The data suggest a heightened susceptibility of the developing brain to hypoxia-ischemia, oxidative stress and excitotoxicity that selectively targets nascent white matter. Glial restricted precursors (GRP), oligodendrocyte progenitor cells (OPC) and immature oligodendrocytes (preOL) seem to be key players in the development of PVL and are the subject of continuing studies. Furthermore, previous studies have identified a subset of CNS tissue that has increased susceptibility to glutamate excitotoxicity as well as a developmental pattern to this susceptibility. Our laboratory is currently investigating the role of oligodendrocyte progenitors in PVL and use cells at the GRP stage of development. We utilize these derived GRP cells in several experimental paradigms to test their response to select stresses consistent with PVL. GRP cells can be manipulated in vitro into OPCs and preOL for transplantation experiments with mouse PVL models and in vitro models of PVL-like insults including hypoxia-ischemia. By using cultured cells and in vitro studies there would be reduced variability between experiments which facilitates interpretation of the data. Cultured cells also allows for enrichment of the GRP population while minimizing the impact of contaminating cells of non-GRP phenotype.
doi:10.3791/3462
PMCID: PMC3399460  PMID: 22760029
Neuroscience;  Issue 64;  Physiology;  Medicine;  periventricular leukomalacia;  oligodendrocytes;  glial restricted precursors;  spinal cord;  cell culture

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