title: STAT3-mediated astrogliosis protects myelin development in neonatal brain injury.
abstract: OBJECTIVE
  Pathological findings in neonatal brain injury associated with preterm birth include focal and/or diffuse white matter injury (WMI). Despite the heterogeneous nature of this condition, reactive astrogliosis and microgliosis are frequently observed. Thus, molecular mechanisms by which glia activation contribute to WMI were investigated.
  
  
  METHODS
  Postmortem brains of neonatal brain injury were investigated to identify molecular features of reactive astrocytes. The contribution of astrogliosis to WMI was further tested in a mouse model in genetically engineered mice.
  
  
  RESULTS
  Activated STAT3 signaling in reactive astrocytes was found to be a common feature in postmortem brains of neonatal brain injury. In a mouse model of neonatal WMI, conditional deletion of STAT3 in astrocytes resulted in exacerbated WMI, which was associated with delayed maturation of oligodendrocytes. Mechanistically, the delay occurred in association with overexpression of transforming growth factor (TGF)β-1 in microglia, which in healthy controls decreased with myelin maturation in an age-dependent manner. TGFβ-1 directly and dose-dependently inhibited the maturation of purified oligodendrocyte progenitors, and pharmacological inhibition of TGFβ-1 signaling in vivo reversed the delay in myelin development. Factors secreted from STAT3-deficient astrocytes promoted elevated TGFβ-1 production in cultured microglia compared to wild-type astrocytes.
  
  
  CONCLUSIONS
  These results suggest that myelin development is regulated by a mechanism involving crosstalk between microglia and oligodendrocyte progenitors. Reactive astrocytes may modify this signaling in a STAT3-dependent manner, preventing the pathological expression of TGFβ-1 in microglia and the impairment of oligodendrocyte maturation.
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, CA, USA.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nobuta
authors.forename: Cristina A
authors.initials: CA
authors.lastname: Ghiani
authors.forename: Pablo M
authors.initials: PM
authors.lastname: Paez
authors.forename: Vilma
authors.initials: V
authors.lastname: Spreuer
authors.forename: Hongmei
authors.initials: H
authors.lastname: Dong
authors.forename: Rose A
authors.initials: RA
authors.lastname: Korsak
authors.forename: Armine
authors.initials: A
authors.lastname: Manukyan
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Li
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
authors.forename: Michael V
authors.initials: MV
authors.lastname: Sofroniew
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Campagnoni
authors.forename: Jean
authors.initials: J
authors.lastname: de Vellis
authors.forename: James A
authors.initials: JA
authors.lastname: Waschek
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D001930:Brain Injuries / Q000150:complications* / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000188:drug therapy / Q000209:etiology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism*; D011180:Postmortem Changes; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051899:Smad2 Protein / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D017077:Culture Media, Conditioned; D004149:Dioxoles; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D018125:Receptors, Transforming Growth Factor beta; D050796:STAT3 Transcription Factor; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1