Traumatically injured astrocytes release a proteomic signature modulated by STAT 3‐dependent cell survival
Open accessAbstract
Molecular markers associated with CNS injury are of diagnostic interest. Mechanical trauma generates cellular deformation associated with membrane permeability with unknown molecular consequences. We used an in vitro model of stretch‐injury and proteomic analyses to determine protein changes in murine astrocytes and their surrounding fluids. Abrupt pressure‐pulse stretching resulted in the rapid release of 59 astrocytic proteins with profiles reflecting cell injury and cell death, i.e., mechanoporation and cell lysis. This acute trauma‐release proteome was overrepresented with metabolic proteins compared with the uninjured cellular proteome, bearing relevance for post‐traumatic metabolic depression. Astrocyte‐specific deletion of signal transducer and activator of transcription 3 (STAT3‐CKO) resulted in reduced stretch‐injury tolerance, elevated necrosis and increased protein release. Consistent with more lysed cells, more protein complexes, nuclear and transport proteins were released from STAT3‐CKO versus nontransgenic astrocytes. STAT3‐CKO astrocytes had reduced basal expression of GFAP, lactate dehydrogenase B (LDHB), aldolase C (ALDOC), and astrocytic phosphoprotein 15 (PEA15), and elevated levels of tropomyosin (TPM4) and α actinin 4 (ACTN4). Stretching caused STAT3‐dependent cellular depletion of PEA15 and GFAP, and its filament disassembly in subpopulations of injured astrocytes. PEA15 and ALDOC signals were low in injured astrocytes acutely after mouse spinal cord crush injury and were robustly expressed in reactive astrocytes 1 day postinjury. In contrast, α crystallin (CRYAB) was present in acutely injured astrocytes, and absent from uninjured and reactive astrocytes, demonstrating novel marker differences among postinjury astrocytes. These findings reveal a proteomic signature of traumatically‐injured astrocytes reflecting STAT3‐dependent cellular survival with potential diagnostic value. GLIA 2016;64:668–694
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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 [30]
The Results section ('Acute STAT3 activation is important for cell integrity and apoptosis after astrocyte injury'; page unavailable) reports that STAT3-deficient astrocytes survived mechanical stretching less well than controls. The paper also reports protective effects after spinal cord injury, but the cited evidence does not establish a benefit of STAT3-dependent transcription in traumatic brain injury specifically. (LLM, conf=0.85)
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- Authors
- Levine, J., Kwon, E., Paez, P., Yan, W., Czerwieniec, G., Loo, J. A., Sofroniew, M. V., & Wanner, I.
- Affiliations
- University of California, Los Angeles (US)
- University at Buffalo, State University of New York (US)
- Corresponding author
- Wanner, Ina‐Beate
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2015-12-19
- Volume
- 64
- Issue
- 5
- Pages
- 668-694
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- PMC
- PMC4805454
- OpenAlex
- W2214778242
- Cited by
- 76
- References
- 95
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 10 · 2023: 4 · 2022: 11 · 2021: 10 · 2020: 4 · 2019: 7 · 2018: 5 · 2017: 6 · 2016: 5
- FWCI
- 3.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1R21NS072606 to IBW; R01NS057624 to MVS; and R01GM104610 to JAL)
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Topics
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Trauma, Hemostasis, Coagulopathy, Resuscitation
- Keywords
- astrocytes, traumatic brain injury, stretch injury, mechanoporation, cell lysis, proteomic signatures, STAT3, cell survival, PEA-15, glial fibrillary acidic protein, reactive astrocytes, alpha-crystallin, alphaB-crystallin, metabolic depression, cell death, diagnostic biomarkers
- MeSH terms
- Animals, Apolipoproteins E, Astrocytes, Cells, Cultured, Cerebral Cortex, Disease Models, Animal, Mice, Inbred C57BL, Peptide Fragments, Mass Spectrometry, Spinal Cord Injuries, Stress, Mechanical, Signal Transduction, Mice, Knockout, Proteomics, Green Fluorescent Proteins, STAT3 Transcription Factor, Mice, Transcriptome
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