title: Endogenous CNTF mediates stroke-induced adult CNS neurogenesis in mice.
abstract: Focal brain ischemia in adult rats rapidly and robustly induces neurogenesis in the subventricular zone (SVZ) but there are few and inconsistent reports in mice, presenting a hurdle to genetically investigate the endogenous neurogenic regulators such as ciliary neurotrophic factor (CNTF). Here, we first provide a platform for further studies by showing that middle cerebral artery occlusion in adult male C57BL/6 mice robustly enhances neurogenesis in the SVZ only under very specific conditions, i.e., 14days after a 30min occlusion. CNTF expression paralleled changes in the number of proliferated, BrdU-positive, SVZ cells. Stroke-induced proliferation was absent in CNTF-/- mice, suggesting that it is mediated by CNTF. MCAO-increased CNTF appears to act on C cell proliferation and by inducing FGF2 expression but not via EGF expression or Notch1 signaling of neural stem cells in the SVZ. CNTF is unique, as expression of other gp130 ligands, IL-6 and LIF, did not predict SVZ proliferation or showed no or only small compensatory increases in CNTF-/- mice. Expression of tumor necrosis factor-α, which can inhibit neurogenesis, and the presence of leukocytes in the SVZ were inversely correlated with neurogenesis, but pro-inflammatory cytokines did not affect CNTF expression in cultured astrocytes. These results suggest that slowly up-regulated CNTF in the SVZ mediates stroke-induced neurogenesis and is counteracted by inflammation. Further pharmacological stimulation of endogenous CNTF might be a good therapeutic strategy for cell replacement after stroke as CNTF regulates normal patterns of neurogenesis and is expressed almost exclusively in the nervous system.
authors.affiliation: Kentucky Spinal Cord Injury Research Center, University of Louisville, KY 40292, USA; Department of Neurological Surgery, University of Louisville, KY 40292, USA.
authors.forename: Seong Su
authors.initials: SS
authors.lastname: Kang
authors.affiliation: Kentucky Spinal Cord Injury Research Center, University of Louisville, KY 40292, USA; Department of Neurological Surgery, University of Louisville, KY 40292, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Keasey
authors.affiliation: Kentucky Spinal Cord Injury Research Center, University of Louisville, KY 40292, USA; Department of Neurological Surgery, University of Louisville, KY 40292, USA; Department of Pharmacology and Toxicology, University of Louisville, KY 40292, USA.
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Arnold
authors.affiliation: Kentucky Spinal Cord Injury Research Center, University of Louisville, KY 40292, USA; Department of Neurological Surgery, University of Louisville, KY 40292, USA.
authors.forename: Rollie
authors.initials: R
authors.lastname: Reid
authors.affiliation: Kentucky Spinal Cord Injury Research Center, University of Louisville, KY 40292, USA; Department of Neurological Surgery, University of Louisville, KY 40292, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Geralds
authors.affiliation: Kentucky Spinal Cord Injury Research Center, University of Louisville, KY 40292, USA; Department of Neurological Surgery, University of Louisville, KY 40292, USA; Department of Pharmacology and Toxicology, University of Louisville, KY 40292, USA. Electronic address: theo.hagg@louisville.edu.
authors.forename: Theo
authors.initials: T
authors.lastname: Hagg
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology; D001921:Brain / Q000503:physiopathology*; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery; D007962:Leukocytes / Q000502:physiology; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000473:pathology / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology*; D015213:Neuroimmunomodulation / Q000502:physiology; D055153:Stem Cell Niche / Q000502:physiology*; D020521:Stroke / Q000473:pathology / Q000503:physiopathology*
chemical_list: D020934:Ciliary Neurotrophic Factor