BDNF Increases the Phagocytic Activity in Cultured Iris Pigment Epithelial Cells

Yoshida, Hayato; Tomita, Hiroshi; Sugano, Eriko; Isago, Hiroaki; Ishiguro, Sei-ichi; Tamai, Makoto

doi:10.1247/csf.07025

Cited by 3 publications

(2 citation statements)

References 31 publications

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“…It is only known that basic FGF rescued the phagocytic defect in the RCS RPE cells . BDNF enhanced the phagocytic activity of cultured macrophages and iris pigment epithelial cells . GDNF increased the phagocytosis ability of primary rat microglia .…”

Section: Discussionmentioning

confidence: 99%

Human umbilical tissue-derived cells rescue retinal pigment epithelium dysfunction in retinal degeneration

Cao

Murat

et al. 2015

Stem Cells

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Retinal pigment epithelium (RPE) cells perform many functions crucial for retinal preservation and vision. RPE cell dysfunction results in various retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration (AMD). Currently, there are no effective treatments for retinal degeneration except for a small percentage of individuals with exudative AMD. Cell therapies targeting RPE cells are being developed in the clinic for the treatment of retinal degeneration. Subretinal injection of human umbilical tissue-derived cells (hUTC) in the Royal College of Surgeons (RCS) rat model of retinal degeneration was shown to preserve photoreceptors and visual function. However, the precise mechanism remains unclear. Here, we demonstrate that hUTC rescue phagocytic dysfunction in RCS RPE cells in vitro. hUTC secrete receptor tyrosine kinase (RTK) ligands brain-derived neurotrophic factor (BDNF), hepatocyte growth factor (HGF), and glial cell-derived neurotrophic factor (GDNF), as well as opsonizing bridge molecules milk-fat-globule-epidermal growth factor 8 (MFG-E8), growth arrest-specific 6 (Gas6), thrombospondin (TSP)-1, and TSP-2. The effect of hUTC on phagocytosis rescue in vitro is mimicked by recombinant human proteins of these factors and is abolished by siRNAtargeted gene silencing in hUTC. The bridge molecules secreted from hUTC bind to the photoreceptor outer segments and facilitate their ingestion by the RPE. This study elucidates novel cellular mechanisms for the repair of RPE function in retinal degeneration through RTK ligands and bridge molecules, and demonstrates the potential of using hUTC for the treatment of retinal degenerative diseases. STEM CELLS 2016;34:367-379 SIGNIFICANCE STATEMENTRetinal degeneration is a leading cause of blindness. There is currently no effective treatment. Retinal pigment epithelium (RPE) play a pivotal role in retinal preservation. The phagocytic function of the RPE is crucial for the integrity of the light-sensing photoreceptors, thus vision. We previously reported that subretinal injection of human umbilical tissue-derived cells (hUTC) in a rodent model of retinal degeneration preserved photoreceptors and vision with an unknown mechanism. Here, we report that hUTC can rescue RPE phagocytic dysfunction through the release of receptor tyrosine kinase ligands and bridge molecules. This study identifies novel mechanisms of a cell-based therapy for correcting the RPE dysfunction in retinal degeneration, suggesting that hUTC may provide utility in treating patients with retinal degenerative diseases, such as AMD and retinitis pigmentosa.

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Section: Discussionmentioning

confidence: 99%

Human umbilical tissue-derived cells rescue retinal pigment epithelium dysfunction in retinal degeneration

Cao

Murat

et al. 2015

Stem Cells

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“…The introduction of anti-vascular endothelial growth factor therapies is leading to meaningful reductions in patients with wet AMD. Various factors, such as the accumulation of unprocessed cellular debris [ 4 , 5 , 6 ] and increased oxidative stress [ 7 , 8 , 9 ], caused by dysfunction of retinal pigment epithelium (RPE) cells, are implicated in the development of dry AMD [ 10 ], for which no effective treatment has yet been developed.…”

Section: Introductionmentioning

confidence: 99%

SIG-1451, a Novel, Non-Steroidal Anti-Inflammatory Compound, Attenuates Light-Induced Photoreceptor Degeneration by Affecting the Inflammatory Process

Kikuchi

Sugano

Yuki

et al. 2022

IJMS

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Age-related macular degeneration is a progressive retinal disease that is associated with factors such as oxidative stress and inflammation. In this study, we evaluated the protective effects of SIG-1451, a non-steroidal anti-inflammatory compound developed for treating atopic dermatitis and known to inhibit Toll-like receptor 4, in light-induced photoreceptor degeneration. SIG-1451 was intraperitoneally injected into rats once per day before exposure to 1000 lx light for 24 h; one day later, optical coherence tomography showed a decrease in retinal thickness, and electroretinogram (ERG) amplitude was also found to have decreased 3 d after light exposure. Moreover, SIG-1451 partially protected against this decrease in retinal thickness and increase in ERG amplitude. One day after light exposure, upregulation of inflammatory response-related genes was observed, and SIG-1451 was found to inhibit this upregulation. Iba-1, a microglial marker, was suppressed in SIG-1451-injected rats. To investigate the molecular mechanism underlying these effects, we used lipopolysaccharide (LPS)-stimulated rat immortalised Müller cells. The upregulation of C-C motif chemokine 2 by LPS stimulation was significantly inhibited by SIG-1451 treatment, and Western blot analysis revealed a decrease in phosphorylated I-κB levels. These results indicate that SIG-1451 indirectly protects photoreceptor cells by attenuating light damage progression, by affecting the inflammatory responses.

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SIG-1451, A Novel, Non-Steroidal Anti-Inflammatory Compound, Attenuates Light-Induced Photoreceptor Degeneration by Inhibiting Microglial Activation

Kikuchi¹,

Sugano²,

Yuki³

et al. 2022

Preprint

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Age-related macular degeneration is a progressive retinal disease that is associated with factors such as oxidative stress, decreased phagocytic activity, and inflammation. In this study, we evaluated the protective effects of SIG-1451, a non-steroidal anti-inflammatory drug developed for treating atopic dermatitis and known to inhibit toll-like receptor 4, on light-induced photoreceptor degeneration. SIG-1451 was intraperitoneally injected into rats once a day before exposure to 1000 lx light for 24 h; one day later, optical coherence tomography showed a decrease in retinal thickness, and electroretinogram (ERG) amplitude was also found to have decreased 3 d after light exposure. Moreover, SIG-1451 protected against this decrease in retinal thickness and increase in ERG am-plitude. One day after light exposure, upregulation of inflammatory response-related genes was observed, and SIG-1451 was found to inhibit this upregulation. Iba-1, a microglial marker, was suppressed in SIG-1451-injected rats. To investigate the molecular mechanism underlying these effects, we used lipopolysaccharide (LPS)-stimulated rat immortalised Müller cells. The upregu-lation of C-C motif chemokine 2　by LPS stimulation was significantly inhibited by SIG-1451 treatment, and western blot analysis revealed a decrease in phosphorylated I-κB levels. These results indicate that SIG-1451 protects photoreceptor cells by attenuating light damage progression through inhibiting inflammatory responses.

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BDNF Increases the Phagocytic Activity in Cultured Iris Pigment Epithelial Cells

Cited by 3 publications

References 31 publications

Human umbilical tissue-derived cells rescue retinal pigment epithelium dysfunction in retinal degeneration

Human umbilical tissue-derived cells rescue retinal pigment epithelium dysfunction in retinal degeneration

SIG-1451, a Novel, Non-Steroidal Anti-Inflammatory Compound, Attenuates Light-Induced Photoreceptor Degeneration by Affecting the Inflammatory Process

SIG-1451, A Novel, Non-Steroidal Anti-Inflammatory Compound, Attenuates Light-Induced Photoreceptor Degeneration by Inhibiting Microglial Activation

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