Inflamed In Vitro Retina: Cytotoxic Neuroinflammation and Galectin-3 Expression

Bauer, Patrik; Zalis, Marina Castro; Abdshill, Hodan; Deierborg, Tomas; Johansson, Fredrik; Englund-Johansson, Ulrica

doi:10.1371/journal.pone.0161723

Cited by 21 publications

(10 citation statements)

References 77 publications

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“…In contrast to our study, where no macroglial response was noted in any of the groups, Klemm et al recently postulated a strong reduction of macroglial response in hypoxia‐stressed and hypothermia‐treated cultivated rat retinas . Another model of cultivated postnatal mouse retinas shows that an increasing macroglial response during cultivation does not additionally increase the apoptosis in the retina . Those studies strengthen the fact that the explantation procedure indeed has an impact on the macroglial response in porcine tissue .…”

Section: Discussioncontrasting

confidence: 52%

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Oxidative stress‐induced retinal damage is prevented by mild hypothermia in an ex vivo model of cultivated porcine retinas

Mueller‐Buehl

Doepper

Grauthoff

et al. 2020

Clinical Exper Ophthalmology

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Background Hydrogen peroxide (H2O2) can be used in vitro to simulate oxidative stress. In retinal organ cultures, H2O2 induces strong neurodegeneration of the retina. It is known that oxidative stress plays a role in the development of several retinal diseases including glaucoma and ischemia. Thus, we investigated whether processes underlying oxidative stress can be prevented by hypothermia using an ex vivo organ culture model of porcine retinas. Methods Porcine retinal explants were cultivated for 5 and 8 days. Oxidative stress was induced via 300 μM H2O2 on day 1 for 3 hours. Hypothermia treatment at 30°C was applied simultaneously with H2O2, for 3 hours. Retinal ganglion cells (RGCs), apoptosis, bipolar and cholinergic amacrine cells, microglia and macroglia were evaluated immunohistologically. Apoptosis rate was additionally analysed via western blot. Results Reduced apoptosis rates through hypothermia led to a preservation of RGCs (P < .001). Amacrine cells were rescued after hypothermia treatment (P = .17), whereas bipolar cells were only protected partly. Additionally, at 8 days, microglial response due to oxidative stress was completely counteracted via hypothermia (P < .001). Conclusions H2O2 induced strong degenerative processes in porcine retinas. The role of oxidative stress in the progression of retinal diseases makes this ex vivo organ culture model suitable to investigate new therapeutic approaches. In the present study, the damaging effect of H2O2 to several retinal cell types was counteracted or strongly alleviated through hypothermia treatment. Especially RGCs, which are affected in glaucoma disease, were protected due to a reduced apoptosis rate through hypothermia.

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Section: Discussioncontrasting

confidence: 52%

“…Besides the porcine retina model, there are several models of ex vivo cultivated retinas of different species, such as mice or rats . The investigation of macroglial response in cultivated mouse or rat retinas seems to be more successful than in cultivated porcine retinas.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress‐induced retinal damage is prevented by mild hypothermia in an ex vivo model of cultivated porcine retinas

Mueller‐Buehl

Doepper

Grauthoff

et al. 2020

Clinical Exper Ophthalmology

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“…High-magnification images showed that Lgals3 + cells were the stromal cells, and they never costained with IB4 + endothelial cells ( Figure 7A, blowup). Lgals3 also marks active microglial cells (56), but costaining with Aif1 indicated that although some microglia were present, most cells in the RAP lesions were Aif1 -, further supporting a Müller glia origin ( Figure 7A). RPE cells also express Sox9 (57); thus it was possible that RPE cells are the cellular origin of the RAP lesions.…”

Section: Resultsmentioning

confidence: 79%

Rb1/Rbl1/Vhl loss induces mouse subretinal angiomatous proliferation and hemangioblastoma

Wei¹,

Ren²,

Kong³

et al. 2019

JCI Insight

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vascular plexuses, including the superficial vascular plexus (SVP) in the nerve fiber layer, deep vascular plexus (DVP) in the outer plexiform layer (OPL), and intermediate vascular plexus (IVP) in the inner plexiform layer (16).The origin of the true tumorigenic cell type in RCH and RAP is controversial. This reflects the dearth of human samples available for histopathological analyses, limiting the vast majority of studies to observations in intact human eyes. In RCH, early work referred to an astrocytic component (17). More recently, but with only 3 cases, 2 groups reported that glial fibrillary acidic protein-positive (GFAP + ) glial cells contribute to human RCH (18,19). Thus, the cell of origin of human RCH needs further investigation.Deleting Vhl in murine retina delays regression of hyaloid vessels and inhibits retinal angiogenesis, which depend on the associated high levels of 21). Paradoxically, therefore, high Hif does not induce RCH, but instead inhibits retinal angiogenesis in the murine Vhl -/retina. Deleting Vhl in all retinal cells and vascular endothelial cells using UBC-Cre ER also suppresses retinal angiogenesis (22). Deleting Vhl in specific retinal cell types, such as amacrine or horizontal interneurons (23), rods (24), cones (25), or retinal pigment epithelium (RPE) cells (26), also does not induce RCH. Although removing Vhl in murine hemangioblasts using stem cell leukemia-Cre ER (Scl-Cre ER ) triggered some features of early-stage RCH, including dilated tortuous vessels, vascular leakage, and foamy stromal cell clusters, histologically it did not cause any neovascularization or hemangioblastoma structures in the retina (27). Thus, it remains unclear why the Vhl -/retina lacks vascular overgrowth and RCH. One possibility is that inhibitors interfere with Hif activity. Indeed, an SNP microarray study implicated several cell cycle genes in the pathogenesis of hemangioblastoma, including the retinoblastoma repressor (Rb1) (28). Inactivating Vhl plus additional tumor suppressors (Rb1 and tumor protein p53; Tp53) can induce CCRCC (29). However, inhibitors that block angiogenesis in the Vhl -/murine retina are unknown.In addition to angiogenesis, autophagy is important for hypoxia adaptation because it captures and degrades intracellular components to sustain metabolism and homeostasis (30). Hypoxia-induced autophagy requires the constitutive expression of beclin 1 (Becn1) and autophagy related 5 (Atg5) and the Hif1-dependent expression of Bnip3/Bnip3L (30,31). Autophagy has been observed in human RCH (32), but its role in the Vhl -/murine retina is unclear.Retinoblastoma is the most common pediatric intraocular tumor. Rb1 regulates cell cycle, cell death, and many other cellular processes in part by inhibiting the E2f transcription factors (33). Loss of Rb1 and its relative Rbl1 (also called p107) in the retina causes mouse retinoblastoma (34-36). In the Rb1/Rbl1-null retina, all differentiating cells divide ectopically, excitatory neurons (ganglion cells, bipolar cells, rods, and cones) underg...

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“…The findings of our study demonstrated that the expression pattern of Gal-3 was significantly enhanced as compared to the controls in serum ( Figures 2 , 3 ) as well as CSF samples ( Figures 6 , 7 ) of AD and ALS patients. This enhanced expression of Gal-3 can be attributed to the activation and regulation of immune system in AD and ALS patients ( Filer et al, 2009 ; Bauer et al, 2016 ; Yip et al, 2017 ). However, the difference in Gal-3 expression in serum ( Figure 4 ) as well as CSF samples ( Figure 8 ) between AD and ALS patients was not significant.…”

Section: Resultsmentioning

confidence: 99%

Investigation of Gal-3 Expression Pattern in Serum and Cerebrospinal Fluid of Patients Suffering From Neurodegenerative Disorders

Ashraf

Baeesa

2018

Front. Neurosci.

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We performed this study to investigate the possibility of a definitive pattern of Galectin-3 (Gal-3) expression in the cerebrospinal fluid (CSF) and serum of Alzheimer’s disease (AD) and Amyotrophic Lateral Sclerosis (ALS) patients. In our study, we collected the CSF and serum samples of 31 AD patients, 19 ALS patients and 50 normal healthy subjects (controls). Quantitative ELISA measured Gal-3 concentrations in CSF and serum samples. A comparative analysis was performed to analyze and understand the Gal-3 expression pattern. A number of neuropsychological assessments and statistical analyses were carried out to validate our findings. Recent researches have established the role of galectins in various neurodegenerative disorders (NDDs), but a definitive pattern of galectin expression is still elusive. A significant difference was observed in serum and CSF Gal-3 concentrations between AD patients and healthy controls. The difference in serum and CSF Gal-3 concentrations between ALS patients vs. controls was lesser as compared to AD patients vs. controls. The difference in serum and CSF Gal-3 concentrations of AD vs. ALS patients was not significant. The MMSE score and serum and CSF Gal-3 concentrations in AD and ALS patients, and controls exhibited a significant positive correlation. The findings of the present study are expected to provide an insight into the definitive pattern of Gal-3 expression in AD and ALS patients, and might thus establish Gal-3 as a strong biomarker. This in turn will open up new and promising research avenues targeting the expression of galectins to modulate the progression of NDDs, and pave the way for novel therapeutic options.

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Inflamed In Vitro Retina: Cytotoxic Neuroinflammation and Galectin-3 Expression

Cited by 21 publications

References 77 publications

Oxidative stress‐induced retinal damage is prevented by mild hypothermia in an ex vivo model of cultivated porcine retinas

Oxidative stress‐induced retinal damage is prevented by mild hypothermia in an ex vivo model of cultivated porcine retinas

Rb1/Rbl1/Vhl loss induces mouse subretinal angiomatous proliferation and hemangioblastoma

Investigation of Gal-3 Expression Pattern in Serum and Cerebrospinal Fluid of Patients Suffering From Neurodegenerative Disorders

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