Müller Cell-Derived PEDF Mediates Neuroprotection via STAT3 Activation

Eichler, Wolfdietrich; Savkovic-Cvijic, Helena; Bürger, Susanne; Beck, Mike; Schmidt, Manuela; Wiedemann, Peter; Reichenbach, Andreas; Unterlauft, Jan Darius

doi:10.1159/000485537

Cited by 27 publications

(12 citation statements)

References 62 publications

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“…Both PEDF and VEGF-AA, which were found to be significantly upregulated after TNFα priming of MSCs, are known neuroprotective agents for injured RGCs. Müller cells exert a neuroprotective effect on RGCs through the secretion of PEDF, 39 while delivery of PEDF into retinal cultures or rat eyes after optic nerve crush leads to significant RGC neuroprotection. 40 Delivery of VEGF into ocular hypertensive eyes leads to significant RGC neuroprotection while also upregulating PEDF.…”

Section: Discussionmentioning

confidence: 99%

TNFα-Mediated Priming of Mesenchymal Stem Cells Enhances Their Neuroprotective Effect on Retinal Ganglion Cells

Mead

Chamling

Zack

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Citation: Mead B, Chamling X, Zack DJ, Ahmed Z, Tomarev S. TNFα-mediated priming of mesenchymal stem cells enhances their neuroprotective effect on retinal ganglion cells. Invest Ophthalmol Vis Sci. 2020;61(2):6. https://doi.org/10.1167/iovs.61.2.6 PURPOSE.To determine whether priming of bone marrow mesenchymal stem cells (MSCs) by signals from injured retina, particularly tumor necrosis factor α (TNFα), increase their exosomes' neuroprotective efficacy on retinal ganglion cells (RGCs). METHODS.MSCs were primed with retinal cell culture conditioned medium, with or without the TNFα blocker etanercept or TNFα prior to isolation of exosomes. MSC conditioned medium or exosomes were added to rat retinal cultures or human stem cell-derived retinal ganglion cell (hRGC) cultures, and RGC neuroprotective effects were quantified. Luminex assays were used to compare primed versus unprimed exosomes. RESULTS.MSC conditioned medium and exosomes exerted a significant neuroprotective effect on injured rat and hRGC. This effect was significantly increased after MSCs were primed with retinal conditioned medium or TNFα. Blocking of TNFα signaling with etanercept prevented priming-induced RGC neuroprotective efficacy. Priming increased Pigment epithelium-derived factor (PEDF) and VEGF-AA exosomal abundance.CONCLUSIONS. MSC exosomes promote RGC survival not just in rodent retinal cultures but also with hRGC. Their efficacy can be further enhanced through TNFα priming with the mechanism of action potentially mediated, at least in part, through increased levels of PEDF and VEGF-AA.

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Section: Discussionmentioning

confidence: 99%

TNFα-Mediated Priming of Mesenchymal Stem Cells Enhances Their Neuroprotective Effect on Retinal Ganglion Cells

Mead

Chamling

Zack

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…Reactive oxygen species lowering has shown to be helpful in protecting neuronal degeneration and favoring the expression of protective factors like compact myelin proteins [93]. Retinal ganglion cell survival is also promoted by PEDF (pigment epithelium-derived factor) via STAT3 (signal transduction and activator of transcription 3) activation secreted by Müller cells [94].…”

Section: Pathophysiology Of Diabetic Retinopathymentioning

confidence: 99%

Oxidative Stress as the Main Target in Diabetic Retinopathy Pathophysiology

Olvera-Montaño

Alberto

Navarro-Partida

et al. 2019

Journal of Diabetes Research

120

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Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus (DM) causing vision impairment even at young ages. There are numerous mechanisms involved in its development such as inflammation and cellular degeneration leading to endothelial and neural damage. These mechanisms are interlinked thus worsening the diabetic retinopathy outcome. In this review, we propose oxidative stress as the focus point of this complication onset.

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“…Pigment epithelium-derived factor (PEDF), a 50-kDa secreted glycoprotein, is widely expressed throughout the body. Previous studies have shown its role in maintaining homeostasis, including neuroprotective, anti-oxidative, anti-inflammatory, anti-tumor and anti-angiogenic [10][11][12][13]. It was found in our previous research that PEDF induced CCMR vessels remodeling--a process known as "pruning", as manifested by increases in lumen diameter and the assembly of VE-cadherin.…”

Section: Introductionmentioning

confidence: 81%

PEDF Induces Native Coronary Collateral Microcirculation Remodeling in a Manner Similar to That of FSS Through Activing Canonical and Non-canonical Notch1 Signaling Pathway Simultaneously

Chen

Liu

Qin

et al. 2020

Preprint

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Background Our previous studies showed that the coronary collateral microcirculation reserve (CCMR) in rat hearts is abundant, but the structure is naturally flawed, which preventing it from continuously providing alternative blood flow to the ischemic myocardium. Further research indicated that pigment epithelium-derived factor (PEDF) can induce CCMR vessels remodeling in a manner similar to that of fluid shear stress (FSS), thus improving compensatory blood flow. However, the specific mechanism remained unclear. Methods We established the rat model of PEDF overexpression in the myocardium and the cardiac explant angiogenesis model in matrigel to identify the role of the canonical and non-canonical Notch1 signaling pathway in the process of PEDF-induced CCMR remodeling. Results: We found that pharmaceutical blockage of Notch1 pathway via γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) would effectively abrogate the remodeling process, including the diameter expansion and adherens junctions reorganization of CCMR induced by PEDF. In vitro, western blot and enzyme activity assay analysis indicated that PEDF treatment simultaneously active the canonical Notch1 pathway (NICD/AKT/eNOS/NO) and non-canonical Notch1 pathway (TMD/VE-cadherin-LAR-Trio complex). To our amusement, using L-Nitromonomethylarginine (L-NMMA) acetate to inhibit endothelial nitric oxide synthase (eNOS) activity could significantly block PEDF-induced the diameter expansion of the nascent blood vessels, but it had little effect on the reassembly of adherens junctions. While activation of non-canonical Notch1 pathway seems to be the cause of adherens junctions remodeling. Blocking of the non-canonical Notch1 pathway canceled PEDF-driven adherens junctions assembly. Conclusions We demonstrate the specific mechanism of PEDF-induced native collateral microcirculation remodeling. PEDF can active the canonical Notch1 pathway signaling pathway to promote lumenal remodeling and, Simultaneously, active non-canonical Notch1 signaling pathway responsible for adherens junctions assembly.

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Müller Cell-Derived PEDF Mediates Neuroprotection via STAT3 Activation

Cited by 27 publications

References 62 publications

TNFα-Mediated Priming of Mesenchymal Stem Cells Enhances Their Neuroprotective Effect on Retinal Ganglion Cells

TNFα-Mediated Priming of Mesenchymal Stem Cells Enhances Their Neuroprotective Effect on Retinal Ganglion Cells

Oxidative Stress as the Main Target in Diabetic Retinopathy Pathophysiology

PEDF Induces Native Coronary Collateral Microcirculation Remodeling in a Manner Similar to That of FSS Through Activing Canonical and Non-canonical Notch1 Signaling Pathway Simultaneously

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