title: Effects of Neonatal Hypoxic-Ischemic Injury and Hypothermic Neuroprotection on Neural Progenitor Cells in the Mouse Hippocampus.
abstract: Neonatal hypoxic-ischemic injury (HI) results in widespread cerebral encephalopathy and affects structures that are essential for neurocognitive function, such as the hippocampus. The dentate gyrus contains a reservoir of neural stem and progenitor cells (NSPCs) that are critical for postnatal development and normal adult function of the hippocampus, and may also facilitate the recovery of function after injury. Using a neonatal mouse model of mild-to-moderate HI and immunohistochemical analysis of NSPC development markers, we asked whether these cells are vulnerable to HI and how they respond to both injury and hypothermic therapy. We found that cleaved caspase-3 labeling in the subgranular zone, where NSPCs are located, is increased by more than 30-fold after HI. The population of cells positive for both proliferating cell nuclear antigen and nestin (PCNA+Nes+), which represent primarily actively proliferating NSPCs, are acutely decreased by 68% after HI. The NSPC population expressing NeuroD1, a marker for NSPCs transitioning to become fate-committed neural progenitors, was decreased by 47%. One week after HI, there was a decrease in neuroblasts and immature neurons in the dentate gyrus, as measured by doublecortin (DCX) immunolabeling, and at the same time PCNA+Nes+ cell density was increased by 71%. NSPCs expressing Tbr2, which identifies a highly proliferative intermediate neural progenitor population, increased by 107%. Hypothermia treatment after HI partially rescues both the acute decrease in PCNA+Nes+ cell density at 1 day after injury and the chronic loss of DCX immunoreactivity and reduction in NeuroD1 cell density measured at 1 week after injury. Thus, we conclude that HI causes an acute loss of dentate gyrus NSPCs, and that hypothermia partially protects NSPCs from HI.
authors.affiliation: Department of Anesthesiology and Critical Care Medicinee, Johns Hopkins Medical Institutes, Baltimore, Md., USA.
authors.forename: Minhye
authors.initials: M
authors.lastname: Kwak
authors.forename: Sanghee
authors.initials: S
authors.lastname: Lim
authors.forename: Eunchai
authors.initials: E
authors.lastname: Kang
authors.forename: Orion
authors.initials: O
authors.lastname: Furmanski
authors.forename: Hongjun
authors.initials: H
authors.lastname: Song
authors.forename: Yun Kyoung
authors.initials: YK
authors.lastname: Ryu
authors.forename: C David
authors.initials: CD
authors.lastname: Mintz
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D018891:Dentate Gyrus / Q000166:cytology / Q000473:pathology*; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology* / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*