STAT3-Mediated astrogliosis protects myelin development in neonatal brain injury
Hiroko Nobuta PhD
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
Interdepartmental Graduate Program in Neuroscience, University of California at Los Angeles, Los Angeles, CA
Search for more papers by this authorCristina A. Ghiani PhD
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
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 authorPablo M. Paez PhD
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
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 authorVilma Spreuer BS
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
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 authorHongmei Dong BS
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
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 authorRose A. Korsak BA
Department of Neurobiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
Search for more papers by this authorArmine Manukyan BS
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
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 authorJiaxi Li BSc
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
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 authorHarry V. Vinters MD
Departments of Pathology and Laboratory Medicine and Neurology, University of California at Los Angeles, Los Angeles, CA
Search for more papers by this authorEric J. Huang MD, PhD
Pathology Service, Veterans Affairs Medical Center, San Francisco, CA
Department of Pathology, University of California at San Francisco, San Francisco, CA
Search for more papers by this authorDavid H. Rowitch MD, PhD
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
Division of Neonatology, University of California at San Francisco, San Francisco, CA
Search for more papers by this authorMichael V. Sofroniew MD, PhD
Department of Neurobiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
Search for more papers by this authorAnthony T. Campagnoni PhD
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
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 authorJean de Vellis PhD
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
Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
Department of Neurobiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
Search for more papers by this authorCorresponding Author
James A. Waschek PhD
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
Interdepartmental Graduate Program in Neuroscience, University of California at Los Angeles, Los Angeles, CA
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 90095-7332Search for more papers by this authorHiroko Nobuta PhD
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
Interdepartmental Graduate Program in Neuroscience, University of California at Los Angeles, Los Angeles, CA
Search for more papers by this authorCristina A. Ghiani PhD
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
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 authorPablo M. Paez PhD
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
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 authorVilma Spreuer BS
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
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 authorHongmei Dong BS
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
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 authorRose A. Korsak BA
Department of Neurobiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
Search for more papers by this authorArmine Manukyan BS
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
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 authorJiaxi Li BSc
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
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 authorHarry V. Vinters MD
Departments of Pathology and Laboratory Medicine and Neurology, University of California at Los Angeles, Los Angeles, CA
Search for more papers by this authorEric J. Huang MD, PhD
Pathology Service, Veterans Affairs Medical Center, San Francisco, CA
Department of Pathology, University of California at San Francisco, San Francisco, CA
Search for more papers by this authorDavid H. Rowitch MD, PhD
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
Division of Neonatology, University of California at San Francisco, San Francisco, CA
Search for more papers by this authorMichael V. Sofroniew MD, PhD
Department of Neurobiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
Search for more papers by this authorAnthony T. Campagnoni PhD
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
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 authorJean de Vellis PhD
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
Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
Department of Neurobiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
Search for more papers by this authorCorresponding Author
James A. Waschek PhD
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
Interdepartmental Graduate Program in Neuroscience, University of California at Los Angeles, Los Angeles, CA
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 90095-7332Search for more papers by this authorAbstract
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
Supporting Information
Additional supporting information can be found in the online version of this article.
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