title: Erythropoietin increases neurogenesis and oligodendrogliosis of subventricular zone precursor cells after neonatal stroke.
abstract: OBJECTIVE
  Stroke is a common cause of neonatal brain injury. The subventricular zone is a lifelong source of newly generated cells in rodents, and erythropoietin (EPO) treatment has shown benefit in different animal models of brain injury. The purpose of this study is to investigate the specific role of exogenous EPO on subventricular zone progenitor cell populations in response to neonatal stroke.
  
  
  METHODS
  Intraventricular injections of green fluorescent protein (GFP)-expressing lentivirus to label subventricular zone precursor cells were made in postnatal day 1 (P1) Long-Evans rats, which then underwent transient middle cerebral artery occlusion on P7. Middle cerebral artery occlusion and sham rats were treated with either vehicle or EPO (1000 U/kg) at reperfusion, 24 hours, and 7 days later. The density of double-labeled DCx+/GFP+, NeuN+/GFP+, O4+/GFP+, GFAP+/GFP+, as well as single-labeled GFP+ and Ki67+ cells, was calculated to determine cell fate outcome in the striatum at 72 hours and 2 weeks after stroke.
  
  
  RESULTS
  There was a significant increase in DCx+/GFP+ and NeuN+/GFP+ neurons and O4+/GFP+ oligodendrocyte precursors, with decreased GFAP+/GFP+ astrocytes at both time points in EPO-middle cerebral artery occlusion animals. There was also a significant increase in GFP+ cells and Ki67+ proliferating cells in EPO compared with vehicle-middle cerebral artery occlusion animals.
  
  
  CONCLUSIONS
  These data suggest that subventricular zone neural progenitor cells proliferate and migrate to the site of injury after neonatal stroke and multiple doses of EPO, with a shift in cell fate toward neurogenesis and oligodendrogliosis at both early and late time points. The contribution of local cell proliferation and neurogenesis remains to be determined.
authors: University of California, San Francisco, San Francisco, CA 94143, USA. gonzalezf@peds.ucsf.edu
authors: Fernando F
authors: FF
authors: Gonzalez
authors: Amara
authors: A
authors: Larpthaveesarp
authors: Patrick
authors: P
authors: McQuillen
authors: Nikita
authors: N
authors: Derugin
authors: Michael
authors: M
authors: Wendland
authors: Ruggero
authors: R
authors: Spadafora
authors: Donna M
authors: DM
authors: Ferriero
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001479:Basal Ganglia / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D000089662:Doublecortin Protein; D004921:Erythropoietin / Q000494:pharmacology*; D049452:Green Fluorescent Proteins; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D023421:Models, Animal; D055495:Neurogenesis / Q000187:drug effects*; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D020318:Rats, Long-Evans; D020521:Stroke / Q000209:etiology / Q000473:pathology*; D013997:Time Factors
chemical_list: C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D004921:Erythropoietin; D049452:Green Fluorescent Proteins
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