Get access

STAT3-Mediated astrogliosis protects myelin development in neonatal brain injury

Authors

  • Hiroko Nobuta PhD,

    1. Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    2. Interdepartmental Graduate Program in Neuroscience, University of California at Los Angeles, Los Angeles, CA
    Search for more papers by this author
  • Cristina A. Ghiani PhD,

    1. Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    2. Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    Search for more papers by this author
  • Pablo M. Paez PhD,

    1. Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    2. Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    Search for more papers by this author
  • Vilma Spreuer BS,

    1. Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    2. Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    Search for more papers by this author
  • Hongmei Dong BS,

    1. Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    2. Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    Search for more papers by this author
  • Rose A. Korsak BA,

    1. Department of Neurobiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    Search for more papers by this author
  • Armine Manukyan BS,

    1. Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    2. Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    Search for more papers by this author
  • Jiaxi Li BSc,

    1. Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    2. Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    Search for more papers by this author
  • Harry V. Vinters MD,

    1. Departments of Pathology and Laboratory Medicine and Neurology, University of California at Los Angeles, Los Angeles, CA
    Search for more papers by this author
  • Eric J. Huang MD, PhD,

    1. Pathology Service, Veterans Affairs Medical Center, San Francisco, CA
    2. Department of Pathology, University of California at San Francisco, San Francisco, CA
    Search for more papers by this author
  • David H. Rowitch MD, PhD,

    1. Departments of Pediatrics and Neurosurgery, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA
    2. Division of Neonatology, University of California at San Francisco, San Francisco, CA
    Search for more papers by this author
  • Michael V. Sofroniew MD, PhD,

    1. Department of Neurobiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    Search for more papers by this author
  • Anthony T. Campagnoni PhD,

    1. Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    2. Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    Search for more papers by this author
  • Jean de Vellis PhD,

    1. Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    2. Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    3. Department of Neurobiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    Search for more papers by this author
  • James A. Waschek PhD

    Corresponding author
    1. Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    2. Interdepartmental Graduate Program in Neuroscience, University of California at Los Angeles, Los Angeles, CA
    3. Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
    • University of California at Los Angeles, 635 Charles E. Young Dr. South, Neuroscience Research Bldg Room 345, Los Angeles, CA 90095-7332
    Search for more papers by this author

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.

Interpretation:

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. ANN NEUROL 2012;72:750–765

Get access to the full text of this article

Ancillary