title: Glial-Restricted Precursors Protect Neonatal Brain Slices from Hypoxic-Ischemic Cell Death Without Direct Tissue Contact.
abstract: Glial-Restricted Precursors (GRPs) are tripotential progenitors that have been shown to exhibit beneficial effects in several preclinical models of neurological disorders, including neonatal brain injury. The mechanisms of action of these cells, however, require further study, as do clinically relevant questions such as timing and route of cell administration. Here, we explored the effects of GRPs on neonatal hypoxia-ischemia during acute and subacute stages, using an in vitro transwell co-culture system with organotypic brain slices exposed to oxygen-glucose deprivation (OGD). OGD-exposed slices that were then co-cultured with GRPs without direct cell contact had decreased tissue injury and cortical cell death, as evaluated by lactate dehydrogenase (LDH) release and propidium iodide (PI) staining. This effect was more pronounced when cells were added during the subacute phase of the injury. Furthermore, GRPs reduced the amount of glutamate in the slice supernatant and changed the proliferation pattern of endogenous progenitor cells in brain slices. In summary, we show that GRPs exert a neuroprotective effect on neonatal hypoxia-ischemia without the need for direct cell-cell contact, thus confirming the rising view that beneficial actions of stem cells are more likely attributable to trophic or immunomodulatory support rather than to long-term integration.
authors.affiliation: 1 Kennedy Krieger Institute , Baltimore, Maryland.|2 Department of Neurology, Johns Hopkins University , Baltimore, Maryland.
authors.forename: Romy
authors.initials: R
authors.lastname: Sweda
authors.affiliation: 1 Kennedy Krieger Institute , Baltimore, Maryland.|3 The Hussman Institute for Autism , Baltimore, Maryland.
authors.forename: Andre W
authors.initials: AW
authors.lastname: Phillips
authors.affiliation: 1 Kennedy Krieger Institute , Baltimore, Maryland.
authors.forename: Joel
authors.initials: J
authors.lastname: Marx
authors.affiliation: 1 Kennedy Krieger Institute , Baltimore, Maryland.|2 Department of Neurology, Johns Hopkins University , Baltimore, Maryland.|4 Department of Pediatrics, Johns Hopkins University , Baltimore, Maryland.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Johnston
authors.affiliation: 1 Kennedy Krieger Institute , Baltimore, Maryland.|2 Department of Neurology, Johns Hopkins University , Baltimore, Maryland.|5 Department of Neuroscience, Johns Hopkins University , Baltimore, Maryland.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Wilson
authors.affiliation: 1 Kennedy Krieger Institute , Baltimore, Maryland.|2 Department of Neurology, Johns Hopkins University , Baltimore, Maryland.|4 Department of Pediatrics, Johns Hopkins University , Baltimore, Maryland.
authors.forename: Ali
authors.initials: A
authors.lastname: Fatemi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000941:Antigens / Q000378:metabolism; D001921:Brain / Q000473:pathology*; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D016923:Cell Death; D015687:Cell Hypoxia; D049109:Cell Proliferation; D018920:Coculture Techniques; D000089622:Doublecortin Domain Proteins; D005260:Female; D005947:Glucose / Q000172:deficiency; D005971:Glutamates / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D007770:L-Lactate Dehydrogenase; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology* / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D009924:Organ Culture Techniques; D010100:Oxygen; D011247:Pregnancy; D011509:Proteoglycans / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D001973:Bromodeoxyuridine; D000089622:Doublecortin Domain Proteins; D005947:Glucose; D005971:Glutamates; D007770:L-Lactate Dehydrogenase; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D018696:Neuroprotective Agents; D010100:Oxygen; D011509:Proteoglycans; D000099216:Chondroitin Sulfate Proteoglycan 4