Cited by 105Neonatal and fetal brain pathologyNeuroinflammation and Neurodegeneration MechanismsNeurogenesis and neuroplasticity mechanisms

STAT3‐Mediated astrogliosis protects myelin development in neonatal brain injury

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Nobuta, Hiroko, Ghiani, Cristina A., Paez, Pablo M., Spreuer, Vilma, Dong, Hongmei, Korsak, Rose A., Manukyan, Armine, Li, Jiaxi +7 more·2012·Annals of Neurology

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

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  • Activation of STAT3-dependent transcription is beneficial in neonatal white matter injury, traumatic brain injury, spinal cord injury, and motor neuron injury, but detrimental in AD models.

    “For example, activation of STAT3-dependent transcription is beneficial in neonatal white matter injury47, traumatic brain injury30, spinal cord injury48,49, and motor neuron injury50, but detrimental in AD models42,43.”

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Research works printed but not linked: 3

  1. [43]Skranes J Vangberg TR Kulseng S Clinical findings and white matter abnormalities seen on diffusion tensor imaging in adolescents with very low birth weight Brain 2007 130 654 666 17347255
  2. [50]Defacque H Piquemal D Basset A Transforming growth factor-beta1 is an autocrine mediator of U937 cell growth arrest and differentiation induced by vitamin D3 and retinoids J Cell Physiol 1999 178 109 119 9886497
  3. [62]Messersmith DJ Murtie JC Le TQ Fibroblast growth factor 2 (FGF2) and FGF receptor expression in an experimental demyelinating disease with extensive remyelination J Neurosci Res 2000 62 241 256 11020217 PMC7138084

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Authors
Nobuta, H., Ghiani, C. A., Paez, P. M., Spreuer, V., Dong, H., Korsak, R. A., Manukyan, A., Li, J., Vinters, H. V., Huang, E. J., Rowitch, D. H., Sofroniew, M. V., Campagnoni, A. T., de Vellis, J., & Waschek, J. A.
Affiliations
  • University of California, Los Angeles (US)
  • San Francisco VA Medical Center (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Waschek, James A.
Venue
Annals of Neurology
Publisher
Wiley
Published
2012-08-31
Volume
72
Issue
5
Pages
750-765
ISSN
  • 0364-5134 (ISSN-L)
  • 1531-8249
OpenAlex
W2083567430
Cited by
97
References
64
Citations by year
2026: 5 · 2025: 2 · 2024: 7 · 2023: 7 · 2022: 8 · 2021: 6 · 2020: 6 · 2019: 9 · 2018: 9 · 2017: 12 · 2016: 7 · 2015: 10 · 2014: 5 · 2013: 4
FWCI
5.33
Type
journal article
Language
en
Open access
Locations
  • Annals of Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institute of Neurological Disorders and Stroke (NS057624, R01NS057624, R21NS070580, NS070580)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD057557, HD004612, R03HD057557, P30HD004612)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
STAT3, reactive astrogliosis, white matter injury, neonatal brain injury, preterm birth, myelination, oligodendrocyte maturation, oligodendrocyte progenitors, TGF-β1, microglia, astrocyte-microglia crosstalk, glial activation
MeSH terms
Age Factors, Animals, Animals, Newborn, Astrocytes, Benzamides, Brain Injuries, Cell Differentiation, Cells, Cultured, Dioxoles, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Female, Glial Fibrillary Acidic Protein, Gliosis, Humans, Infant, Infant, Newborn, Lipopolysaccharides, Male, Mice, Inbred C57BL, Myelin Sheath, Postmortem Changes, Stem Cells, Signal Transduction, Culture Media, Conditioned, Receptors, Transforming Growth Factor beta, Mice, Knockout, Gene Expression Regulation, Developmental, Cell Proliferation, STAT3 Transcription Factor, Mice, Smad2 Protein, Transforming Growth Factor beta1

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