Abnormal Reactivity of Müller Cells after Retinal Detachment in Mice Deficient in GFAP and Vimentin

Verardo, Mark R.; Lewis, Geoffrey P.; Takeda, Masatoshi; Linberg, Kenneth A.; Byun, Jiyun; Luna, Gabriel; Wilhelmsson, Ulrika; Pekny, Milos; Chen, Dongfeng; Fisher, Steven K.

doi:10.1167/iovs.07-1474

Cited by 110 publications

(90 citation statements)

References 39 publications

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“…For instance, Vim GFAP dKO mice have a high incidence of mortality when subjected to brain injury (9) and retinal Müller glial endfeet are also especially sensitive to physical injury (53). In contrast, we found that pharmacological delivery of 2 mg/kg of WFA causes knockdown of soluble vimentin and GFAP in injury healing WT mice to levels found in uninjured controls, and this WFA dose did not increase fragility of ocular tissues.…”

Section: Discussionmentioning

confidence: 50%

Withaferin A Targets Intermediate Filaments Glial Fibrillary Acidic Protein and Vimentin in a Model of Retinal Gliosis

Bargagna‐Mohan

Paranthan

Hamza

et al. 2010

Journal of Biological Chemistry

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Gliosis is a biological process that occurs during injury repair in the central nervous system and is characterized by the overexpression of the intermediate filaments (IFs) glial fibrillary acidic protein (GFAP) and vimentin. A common thread in manyThe overexpression of glial fibrillary acidic protein (GFAP) 2 with vimentin is a hallmark of reactive gliosis in the central nervous system (CNS) (1, 2). These intermediate filaments (IFs) are expressed by reactive astrocytes and macro-and microglia during traumatic and inflammatory injury and in a range of CNS degenerative diseases (2). In fact, an enigma of major retinal diseases, including age-related macular degeneration, glaucoma, diabetic retinopathy, and retinopathy of prematurity, is retinal gliosis, for which there is no available clinical treatment (3-5).Important fundamental insights on the structural and mechanical functions of IFs (6, 7) have now been validated in mouse lines deficient in type III IFs (2). These studies have illuminated that, whereas overexpression of vimentin and GFAP during CNS stress response and injury repair contributes to scar formation (8), their deficiency can be protective of tissue functions in certain contexts. For instance, pathogenic angiogenesis is impaired in vimentin-deficient (Vim KO) mice due to the decreased ability of newly formed blood vessels to cross the retinal inner limiting membrane in the model of hypoxia-induced retinal neovascularization (9). Interestingly, that study also identified in vimentin and GFAP double deficient (Vim GFAP dKO) mice, and to a lesser extent in Vim KO mice, that the retinal ganglion layer is highly sensitive to mechanical stress, which was not observed in GFAP KO mice. Pathological neovascularization was also reduced in Vim KO mice in the corneal alkali injury model (10) and delayed vascularization in skin injury model (11), which is attributed to defective vascular endothelial cell integrity (12), because vimentin is the sole type III IF expressed in endothelial cells (13). On the other hand, Vim GFAP dKO mice subjected to spinal cord or brain injury recover favorably with improvement of glial scars (14). In fact, the complete absence of type III IFs in Vim GFAP dKO mice helps promote axonal regeneration and regain ambulatory function after spinal cord injury (15). These Vim GFAP dKO

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Section: Discussionmentioning

confidence: 50%

Withaferin A Targets Intermediate Filaments Glial Fibrillary Acidic Protein and Vimentin in a Model of Retinal Gliosis

Bargagna‐Mohan

Paranthan

Hamza

et al. 2010

Journal of Biological Chemistry

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“…GFAP Ϫ/Ϫ Vim Ϫ/Ϫ mice show reduced reactive gliosis and glial scar formation, a slower healing process with increased loss of neuronal synapses after neurotrauma (172,262), and decreased resistance of the CNS tissue to severe mechanical stresses (142,243). While astrocytes around the CNS lesion in GFAP Ϫ/Ϫ Vim Ϫ/Ϫ mice are comparable to those of wild-type mice with respect to their number and the volume they access (262), they do not develop the typical reactive phenotype characterized by the thickening (hypertrophy) of their main cellular processes (260,262) (FIGURE 8, A AND B).…”

Section: Vimmentioning

confidence: 99%

Astrocyte Reactivity and Reactive Astrogliosis: Costs and Benefits

Pekny

Pekna

2014

Physiological Reviews

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739

576

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Astrocytes are the most abundant cells in the central nervous system (CNS) that provide nutrients, recycle neurotransmitters, as well as fulfill a wide range of other homeostasis maintaining functions. During the past two decades, astrocytes emerged also as increasingly important regulators of neuronal functions including the generation of new nerve cells and structural as well as functional synapse remodeling. Reactive gliosis or reactive astrogliosis is a term coined for the morphological and functional changes seen in astroglial cells/astrocytes responding to CNS injury and other neurological diseases. Whereas this defensive reaction of astrocytes is conceivably aimed at handling the acute stress, limiting tissue damage, and restoring homeostasis, it may also inhibit adaptive neural plasticity mechanisms underlying recovery of function. Understanding the multifaceted roles of astrocytes in the healthy and diseased CNS will undoubtedly contribute to the development of treatment strategies that will, in a context-dependent manner and at appropriate time points, modulate reactive astrogliosis to promote brain repair and reduce the neurological impairment.

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“…The genetic knockouts of IFs, while revealing that they are not essential for development or reproduction (9,10), have drawn more recent attention to their functions in tissue repair and stress response (11,12). Vimentin is the prototypic Type III IF protein that is widely studied because of its involvement in wound healing, fibrosis, angiogenesis, tumor cell differentiation, migration, and metastasis (13)(14)(15)(16)(17)(18). Vimentin plays a critical role in wound repair by providing activated wound fibroblasts during transition to the myofibroblastic phenotype with force generation required for tissue contraction (19).…”

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confidence: 99%

Corneal Antifibrotic Switch Identified in Genetic and Pharmacological Deficiency of Vimentin

Bargagna‐Mohan

Paranthan

Hamza

et al. 2012

Journal of Biological Chemistry

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Background: Withaferin A (WFA) is a vimentin-targeting inhibitor that has potent anti-proliferative activity. Results: WFA protects against corneal fibrosis by down-regulating injury-induced vimentin to exert epithelial cell cycle arrest and inhibit myofibroblast expression, which is a mechanism closely mimicked in vimentin-deficient mice during injury healing. Conclusion: Vimentin is a novel fibrosis target. Significance: Ocular fibrotic conditions that overexpress vimentin could be treatable with WFA.

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Abnormal Reactivity of Müller Cells after Retinal Detachment in Mice Deficient in GFAP and Vimentin

Cited by 110 publications

References 39 publications

Withaferin A Targets Intermediate Filaments Glial Fibrillary Acidic Protein and Vimentin in a Model of Retinal Gliosis

Withaferin A Targets Intermediate Filaments Glial Fibrillary Acidic Protein and Vimentin in a Model of Retinal Gliosis

Astrocyte Reactivity and Reactive Astrogliosis: Costs and Benefits

Corneal Antifibrotic Switch Identified in Genetic and Pharmacological Deficiency of Vimentin

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