STAT3‐Mediated astrogliosis protects myelin development in neonatal brain injury
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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.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [47]
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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.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2012-08-31
- Volume
- 72
- Issue
- 5
- Pages
- 750-765
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC3514566
- 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
- green
- europepmc.org
- 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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