title: Cell-density-dependent regulation of neural precursor cell function.
abstract: Stress-induced reductions of neural precursor cells from the subgranular zone of the hippocampal dentate gyrus have been linked to impaired neurogenesis and cognitive dysfunction. Given the importance of redox state in regulating multiple damage-responsive pathways in the CNS, we hypothesize that oxidative stress plays a major role in affecting neurogenesis and subsequent cognitive function after cell injury/depletion. Using an in vitro system, we showed that the level of reactive oxygen species (ROS), which depend critically on changes in cell density, were significantly higher in neural precursor cells when compared with other primary and transformed cell lines. ROS were significantly elevated ( approximately 4-fold) under low- (<1 x 10(4) cells per cm(2)) versus high-density (>1 x 10(5) cells per cm(2)) conditions. Higher ROS levels found at lower cell densities were associated with elevated proliferation and increased metabolic activity. These ROS were likely a result of altered mitochondrial function that ultimately compromised the growth rate of cells. At high cell densities, intracellular ROS and oxidative damage were reduced in concert with an increased expression of mitochondrial superoxide dismutase 2. Our finding that DNA-damage-induced depletion of neural precursor cells in the subgranular zone of mice also led to increased ROS and altered proliferation validated our in vitro system. Increased ROS and proliferation associated with the reduction of precursor cell numbers both in vitro and in vivo could be reversed with the antioxidant alpha-lipoic acid. These data showed that neural precursor cells were predisposed to microenvironmental cues that regulate redox-sensitive pathways to control cellular proliferation after CNS damage.
authors.affiliation: Departments of Radiation Oncology and Neurological Surgery, University of California, San Francisco, CA 94103. limoli@itsa.ucsf.edu
authors.forename: Charles L
authors.initials: CL
authors.lastname: Limoli
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Rola
authors.forename: Erich
authors.initials: E
authors.lastname: Giedzinski
authors.forename: Sailaja
authors.initials: S
authors.lastname: Mantha
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Huang
authors.forename: John R
authors.initials: JR
authors.lastname: Fike
mesh_terms: D000818:Animals; D002452:Cell Count; D002455:Cell Division; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D016222:Fibroblast Growth Factor 2