Regulation of RhoA by STAT3 coordinates glial scar formation

Raffi, François; Mukaino, Masahiko; Shinozaki, Munehisa; Kumamaru, Hiromi; Kawase, S.; Baudoux, Matthieu; Ishibashi, Toshiki; Kawabata, Soya; Nishiyama, Yuichiro; Sugai, Keiko; Yasutake, Kaori; Okada, Seiji; Nakamura, Masaya; Okano, Hideyuki

doi:10.1083/jcb.201610102

Cited by 71 publications

(52 citation statements)

References 62 publications

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“…TGF-β increases microglia/macrophage and astrocyte activation and fibronectin and laminin deposition [49]. Signal transducer and activator of transcription 3 (STAT3) is also important for establishing the glial scar border that secludes infiltrating cells to the lesion epicenter [51,52]. Previous schools of thought simply classified the glial scar as a maladaptation opposing neurite regrowth.…”

Section: Glial and Fibrotic Scarring After Spinal Cord Injurymentioning

confidence: 99%

Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses

2018

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Deficits in neuronal function are a hallmark of spinal cord injury (SCI) and therapeutic efforts are often focused on central nervous system (CNS) axon regeneration. However, secondary injury responses by astrocytes, microglia, pericytes, endothelial cells, Schwann cells, fibroblasts, meningeal cells, and other glia not only potentiate SCI damage but also facilitate endogenous repair. Due to their profound impact on the progression of SCI, glial cells and modification of the glial scar are focuses of SCI therapeutic research. Within and around the glial scar, cells deposit extracellular matrix (ECM) proteins that affect axon growth such as chondroitin sulfate proteoglycans (CSPGs), laminin, collagen, and fibronectin. This dense deposition of material, i.e., the fibrotic scar, is another barrier to endogenous repair and is a target of SCI therapies. Infiltrating neutrophils and monocytes are recruited to the injury site through glial chemokine and cytokine release and subsequent upregulation of chemotactic cellular adhesion molecules and selectins on endothelial cells. These peripheral immune cells, along with endogenous microglia, drive a robust inflammatory response to injury with heterogeneous reparative and pathological properties and are targeted for therapeutic modification. Here, we review the role of glial and inflammatory cells after SCI and the therapeutic strategies that aim to replace, dampen, or alter their activity to modulate SCI scarring and inflammation and improve injury outcomes.

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Section: Glial and Fibrotic Scarring After Spinal Cord Injurymentioning

confidence: 99%

Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses

2018

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“…Overall, these results improved the possibility that miR-21 could manage the polarization of reactive astrocyte subtype by targeting STAT3. As past research confirmed its importance to recovery from injury by finding that STAT3 regulated glial scar formation (7,10), we would test the role of STAT3 in postacute ISCI.…”

Section: Discussionmentioning

confidence: 98%

“…Characteristic markers for A2s include pentraxin 3 (Ptx3), S100 calcium-binding protein A10 (S100a10), and sphingosine-1-phosphate receptor 3 (S1pr3); and for A1s, histocompatibility 2, D region locus 1 (H2d1), complement component 3 (C3), and serpin family G member 1 (Serping1) (4)]. NF-kB and reactive oxygen species are major regulators of the polarization of A1 from reactive astrocytes, whereas those for A2s may include signal transducer and activator of transcription-3 (STAT3), ras homolog family member A, hypoxia inducible factor 1 subunit a, and erythropoietin (7)(8)(9)(10)(11).…”

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confidence: 99%

Silencing miR‐21 induces polarization of astrocytes to the A2 phenotype and improves the formation of synapses by targeting glypican 6 via the signal transducer and activator of transcription‐3 pathway after acute ischemic spinal cord injury

Chen

et al. 2019

FASEB j.

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Ischemic spinal cord injury (ISCI) results in the motor sensory dysfunction of the limbs below the injury site. In response to the injury, astrocytes develop into neuroprotective astrocytes [(neurotrophic reactive astrocytes (A2s)] to mitigate the damage. MicroRNA (miR)‐21 can promote the development of neuroinflammation in previous studies. Our aim was to investigate the effect of miR‐21 on its polarization. We used the abdominal aortic occlusion model in vivo. Immunohistochemistry was used to detect the distribution of A2s in the spinal cord. We used an oxygen glucose deprivation method to model astrocytes ischemia in vitro and tested proliferation, migration, and excitability of A2s using an 5‐ethynyl ‐2′‐deoxyuridine kit, wound scratch assay, and calcium‐ion probe. After adjustment, we detected the model and target genes of A2s using PCR Western blot, immunofluorescence, and chromatin immunoprecipitation. We demonstrated in vivo that naive astrocytes were transformed into A2s by ischemia. And in vitro miR‐21, which can regulate the signal transducer and activator of transcription‐3 pathway, can transform neurotoxic reactive astrocyte into A2. Moreover, we also verified the mechanism of A2s promoting synaptic formation and nerve growth. miR‐21 is a switch to regulate the polarization of reactive astrocyte, and it promoted synapsis formation and nerites growth after acute ISCI.—Su, Y., Chen, Z., Du, H., Liu, R., Wang, W., Li, H., Ning, B. Silencing miR‐21 induces polarization of astrocytes to the A2 phenotype and improves the formation of synapses by targeting glypican 6 via the signal transducer and activator of transcription‐3 pathway after acute ischemic spinal cord injury. FASEB J. 33, 10859–10871 (2019). http://www.fasebj.org

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“…It is known that RhoA activation is associated with the motility of astrocytes (Zeug et al, ). It has been shown that inhibition of the GTPase RhoA decreases migratory properties of astrocytes (Renault‐Mihara, ). Moreover, it has been shown that astrocytes reduce their processes and retract cytoplasm in response to the reduced activity of RhoA (Brozzi, Arcuri, Giambanco, & Donato, ).…”

Section: Rho Gtpases Control Elongation Of Cell Extensions In Astrocytesmentioning

confidence: 99%

Abnormalities in interactions of Rho GTPases with scaffolding proteins contribute to neurodevelopmental disorders

Reichova

Zatkova

Bačová

et al. 2017

J of Neuroscience Research

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Accumulating evidence suggests that Rho GTPases, together with scaffolding SHANK proteins, and associated signaling pathways play a role in the development of autism symptoms in various conditions. Research data have brought information on multiple intracellular signaling pathways, including Rho-associated protein kinases and serine/threonine-protein kinases involved in cytoskeleton rearranging. Alterations in downstream effectors of GTPase signaling pathways are associated with neurodevelopmental disorders. Bioinformatics and experimental data show that complex genetic and molecular defects (GTPases, actin-binding proteins, kinases, neuropeptides) can result in neuronal remodeling, leading to the functional connectivity deficits that manifest as the heterogeneous autism spectrum phenotype. Finally, the known hormone and neuropeptide oxytocin appears to be a factor for consideration in therapeutic intervention.

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Regulation of RhoA by STAT3 coordinates glial scar formation

Abstract: The transcription factor STAT3 is known to control glial scar formation, but the underlying mechanism is unknown. Renault-Mihara et al. show that inhibition of the small GTPase RhoA by STAT3 coordinates reactive astrocyte dynamics during glial scar formation.

Cited by 71 publications

References 62 publications

Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses

Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses

Silencing miR‐21 induces polarization of astrocytes to the A2 phenotype and improves the formation of synapses by targeting glypican 6 via the signal transducer and activator of transcription‐3 pathway after acute ischemic spinal cord injury

Abnormalities in interactions of Rho GTPases with scaffolding proteins contribute to neurodevelopmental disorders

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