STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury

By J. Herrmann, T. Imura, B. Song, Jingwei Qi, Y. Ao, Thuhien Nguyen, Rose A. Korsak, K. Takeda, Shizuo Akira, M. Sofroniew. Journal of Neuroscience, 2008

912 citations recorded by the source corpus.

Signaling mechanisms that regulate astrocyte reactivity and scar formation after spinal cord injury (SCI) are not well defined. We used the Cre recombinase (Cre)-loxP system under regulation of the mouse glial fibrillary acidic protein (GFAP) promoter to conditionally delete the cytokine and growth factor signal transducer, signal transducer and activator of transcription 3 (STAT3), from astrocytes. After SCI in GFAP-Cre reporter mice, >99% of spinal cord cells that exhibited Cre activity as detected by reporter protein expression were GFAP-expressing astrocytes. Conditional deletion (or knock-out) of STAT3 (STAT3-CKO) from astrocytes in GFAP-Cre-loxP mice was confirmed in vivo and in vitro. In uninjured adult STAT3-CKO mice, astrocytes appeared morphologically similar to those in STAT3+/+ mice except for a partially reduced expression of GFAP. In STAT3+/+ mice, phosphorylated STAT3 (pSTAT3) was not detectable in astrocytes in uninjured spinal cord, and pSTAT3 was markedly upregulated after SCI in astrocytes and other cell types near the injury. Mice with STAT3-CKO from astrocytes exhibited attenuated upregulation of GFAP, failure of astrocyte hypertrophy, and pronounced disruption of astroglial scar formation after SCI. These changes were associated with increased spread of inflammation, increased lesion volume and partially attenuated motor recovery over the first 28 d after SCI. These findings indicate that STAT3 signaling is a critical regulator of certain aspects of reactive astrogliosis and provide additional evidence that scar-forming astrocytes restrict the spread of inflammatory cells after SCI.

Subfields: Cellular and Molecular Neuroscience, Developmental Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/eee186ca90267cc7b31a8de960f4869adf105b2c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. M. Sofroniew
2. M. Pekny
3. M. Pekna
4. E. Hol
5. Y. Ao
6. B. Song
7. A. Tran
8. B. Barres

In Developmental Neuroscience

1. M. Sofroniew
2. M. Pekny
3. M. Pekna
4. E. Hol
5. Y. Ao
6. B. Song
7. C. Farina
8. E. Colombo

In Neurology

1. M. Sofroniew
2. M. Pekny
3. M. Pekna
4. E. Hol
5. S. A. Liddelow
6. Y. Ao
7. B. Barres
8. B. Song

Citations in the corpus

• The Biology of Regeneration Failure and Success After Spinal Cord Injury. (2018, background): “The STAT signaling pathway has also been implicated in astrocytosis to initiate hypertrophy (FIGURE 5A) (165, 291, 408).”
• Astrocyte reactivity and reactive astrogliosis: costs and benefits. (2014, background): “functions of reactive astrocytes and STAT3 signaling in CNS injury and suggest that the demarcation of the lesion area by reactive astrocytes evolved to sequester a potentially toxic lesion environment from the rest of CNS (95, 163, 191, 252), even though this might restrict regenerative responses a”
• Glial Scar Borders Are Formed by Newly Proliferated, Elongated Astrocytes That Interact to Corral Inflammatory and Fibrotic Cells via STAT3-Dependent Mechanisms after Spinal Cord Injury (2013, methodology): “…mice, referred to here as STAT3-CKO mice, were generated using a well characterized mGFAP-Cre, which after SCI targets reporter protein to over 97% of astroglia and no other identifiable cell type, and selectively deletes the signaling molecule STAT3 only from astroglia (Herrmann et al., 2008).”
• Normal aging induces A1-like astrocyte reactivity (2018, background): “This transcription factor is thought to be required for the induction astrocyte gliosis (25, 26).”
• Traumatic Spinal Cord Injury: An Overview of Pathophysiology, Models and Acute Injury Mechanisms (2019, background): “Attenuating astrocyte reactivity and scar formation by blockade of STAT3 activation results in poorer outcomes in SCI (211, 286).”
• Reactive gliosis and the multicellular response to CNS damage and disease (2014, neutral): “or decrease lesion sizes (Brambilla et al., 2005; Herrmann et al., 2008; Okada et al., 2006; Wanner et al., 2013), providing targets for potential intervention.”
• Reactive Astrocytes: Production, Function, and Therapeutic Potential. (2017, background): “Many studies have implicated JAK-STAT3 in scar-forming astrocyte reactivity after acute injury (Herrmann et al., 2008; Anderson et al., 2016; Ceyzériat et al., 2016).”