Involvement of Müller Glial Autoinduction of TGF-β in Diabetic Fibrovascular Proliferation Via Glial–Mesenchymal Transition

Wu, Di; Kanda, Atsuhiro; Liu, Ye; Noda, Kousuke; Murata, Miyuki; Ishida, Susumu

doi:10.1167/iovs.61.14.29

Cited by 25 publications

(19 citation statements)

References 42 publications

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“…TGF-β1 stimulated TGF-β-SNAIL axis induces MG-mesenchymal transition (MET) in the pathogenesis of idiopathic epiretinal membrane in mammals, indicating its roles in retinal fibrosis ( Kanda et al, 2019 ). TGF-β1/2 administration causes increased phosphorylation of SMAD3 and p38MAPK with increased VEGF-A mRNA expression in MG, which has been observed in fibrovascular tissues from patients ( Wu D. et al, 2020 ). TGF-β1 and Notch have been shown to promote MG-mediated retinal gliosis in mice ( Fan et al, 2020 ).…”

Section: Cytokines and The Mgmentioning

confidence: 83%

Regulations of Retinal Inflammation: Focusing on Müller Glia

Chen

Xia

Zeng

et al. 2022

Front. Cell Dev. Biol.

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Retinal inflammation underlies multiple prevalent retinal diseases. While microglia are one of the most studied cell types regarding retinal inflammation, growing evidence shows that Müller glia play critical roles in the regulation of retinal inflammation. Müller glia express various receptors for cytokines and release cytokines to regulate inflammation. Müller glia are part of the blood-retinal barrier and interact with microglia in the inflammatory responses. The unique metabolic features of Müller glia in the retina makes them vital for retinal homeostasis maintenance, regulating retinal inflammation by lipid metabolism, purine metabolism, iron metabolism, trophic factors, and antioxidants. miRNAs in Müller glia regulate inflammatory responses via different mechanisms and potentially regulate retinal regeneration. Novel therapies are explored targeting Müller glia for inflammatory retinal diseases treatment. Here we review new findings regarding the roles of Müller glia in retinal inflammation and discuss the related novel therapies for retinal diseases.

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Section: Cytokines and The Mgmentioning

confidence: 83%

Regulations of Retinal Inflammation: Focusing on Müller Glia

Chen

Xia

Zeng

et al. 2022

Front. Cell Dev. Biol.

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“…Proliferating Müller cells are considered to be a scaffold for neurites to grow on, 7,33 and recently, Müller glial-mesenchymal transition was postulated as an alternative fibrinogenic mechanism associated with membrane formation in PDR. 11 Another recent study showed that proliferation and migration of cultured Müller cells were stimulated by vitreous of PDR patients (Rezzola et al 2021). 34 Together, this provides further evidence for a role of Müller cells in the formation of FVMs in PDR.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Müller glial-mesenchymal transition has been postulated as an alternative fibrinogenic mechanism associated with membrane formation in PDR. 11 More precise knowledge of the molecular mechanisms underlying FVM development and progression may enable novel pharmacological interventions to be identified.…”

Section: Introductionmentioning

confidence: 99%

PDGF as an Important Initiator for Neurite Outgrowth Associated with Fibrovascular Membranes in Proliferative Diabetic Retinopathy

Lefevere

Hove

Sergeys

et al. 2021

Current Eye Research

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Purpose:The formation of fibrovascular membranes (FVMs) is a serious sight-threatening complication of proliferative diabetic retinopathy (PDR) that may result in retinal detachment and eventual blindness. During the formation of these membranes, neurite/process outgrowth occurs in retinal neurons and glial cells, which may both serve as a scaffold and have guiding or regulatory roles. To further understand this process, we investigated whether previously identified candidate proteins, from vitreous of PDR patients with FVMs, could induce neurite outgrowth in an experimental setting. Materials and methods: Retinal explants of C57BL6/N mouse pups on postnatal day 3 (P3) were cultured in poly-L-lysine-and laminin-coated dishes. Outgrowth stimulation experiments were performed with the addition of potential inducers of neurite outgrowth. Automated analysis of neurite outgrowth was performed by measuring β-tubulin-immunopositive neurites using Image J. Expression of PDGF receptors was quantified by RT-PCR in FVMs of PDR patients. Results: Platelet-derived growth factor (PDGF) induced neurite outgrowth in a concentration-dependent manner, whilst neuregulin 1 (NRG1) and connective tissue growth factor (CTGF) did not. When comparing three different PDGF dimers, treatment with PDGF-AB resulted in the highest neurite induction, followed by PDGF-AA and -BB. In addition, incubation of retinal explants with vitreous from PDR patients resulted in a significant induction of neurite outgrowth as compared to non-diabetic control vitreous from patients with macular holes, which could be prevented by addition of CP673451, a potent PDGF receptor (PDGFR) inhibitor. Abundant expression of PDGF receptors was detected in FVMs. Conclusion:Our findings suggest that PDGF may be involved in the retinal neurite outgrowth, which is associated with the formation of FVMs in PDR.

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“…In the present study, immunohistochemistry on vitreous cell block preparations demonstrated a cluster of GFAP-positive cells, suggesting the migration and proliferation of activated glial cells. The major cellular components of epiretinal proliferative tissues include glial cells that induce fibrosis and/or gliosis, the former of which are mediated by myofibroblastic transdifferentiation from glial cells, also known as glial-mesenchymal transition (GMT) seen in idiopathic epiretinal membrane [ 11 ] and proliferative diabetic retinopathy [ 12 ]. GMT is characterized by focal contractile forces exerted by transdifferentiated myofibroblasts with massive collagen production (i.e., fibrosis), generating funduscopically visible wrinkles and folds on the membrane, which would however be apart from the ground-glass-sheet appearance free of such focal contraction in our cases.…”

Section: Discussionmentioning

confidence: 99%

Gliotic opaque posterior hyaloid membrane separation: report of two cases

et al. 2021

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Background To report two cases with idiopathic unilateral diffuse opacification of the posterior hyaloid membrane (PHM) completely separated from the retina, the mechanism of which is possibly due to glial cell proliferation and migration. Case presentation Two Japanese women at age 75 and 84 with no systemic or ocular history developed diffuse opacification in one eye resembling a ground glass sheet almost all over the surface of the PHM, but not within the vitreous gel or fluid. The retinas were funduscopically normal; however, optical coherence tomography demonstrated hyperreflective icicle-like anterior protrusions from the surface of the fovea. The patients received pars plana vitrectomy, resulting in visual improvement. Cell block preparations of the vitreous in one case revealed a cluster of cells immunoreactive for glial fibrillary acidic protein in consistence with gliosis, while denying vitreoretinal lymphoma from lack of atypical cells and vitreous amyloidosis due to no staining for Congo red or direct fast scarlet. The lesions did not recur during follow-up with no new funduscopic abnormalities. Conclusions To our knowledge, this is the first to demonstrate such peculiar cases of vitreous opacity with idiopathic and unilateral onset. Histological assessments revealed the possible pathogenesis of gliotic opaque PHM separation to cause its ground-glass-sheet appearance.

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Involvement of Müller Glial Autoinduction of TGF-β in Diabetic Fibrovascular Proliferation Via Glial–Mesenchymal Transition

Cited by 25 publications

References 42 publications

Regulations of Retinal Inflammation: Focusing on Müller Glia

Regulations of Retinal Inflammation: Focusing on Müller Glia

PDGF as an Important Initiator for Neurite Outgrowth Associated with Fibrovascular Membranes in Proliferative Diabetic Retinopathy

Gliotic opaque posterior hyaloid membrane separation: report of two cases

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