The aim of this study is to investigate the vascular outcome after intravitreal mesenchymal stem cell (MSC) administration in rats without or with damage to the neurovascular unit [transgenic (TGR) rats]. Male Sprague-Dawley (SD) and TGR rats received an intravitreal injection of 2 3 10 4 rat bone marrow-derived MSCs (BMSCs) or human adipose-derived stem cells (ASCs) at postnatal d 30. After 4 wk, vasculature, neuronal function, and gene expression in the retinas were evaluated using retinal morphometry, electroretinography, immunofluorescence, Western blot, and quantitative PCR. Intravitreal administration of rat BMSCs and human ASCs in both SD and TGR eyes induced cataract, loss of pericytes, and increased formation of acellular capillaries. BMSCs remained in the vitreous cavity and did not migrate into the retinas. Intravitreal administration of BMSCs impacted retinal neuronal function in neither SD nor TGR rats. Retinal glial activation, elevation of IL-1b, C3, arginase 1, and heat shock protein 90 were detected in BMSC-injected SD rats. Intravitreal administration of MSCs induces cataract, retinal vasoregression, activation of retinal glial cells, and inflammatory response in rat eyes.-Huang, H.,
Objective Glucosamine, an intermetabolite of the hexosamine biosynthesis pathway (HBP), is a widely used nutritional supplement in osteoarthritis patients, a subset of whom also suffer from diabetes. HBP is activated in diabetic retinopathy (DR). The aim of this study is to investigate the yet unclear effects of glucosamine on DR. Methods In this study, we tested the effect of glucosamine on vascular and neuronal pathology in a mouse model of streptozotocin-induced DR in vivo and on cultured endothelial and Müller cells to elucidate the underlying mechanisms of action in vitro . Results Glucosamine did not alter the blood glucose or HbA 1c levels in the animals, but induced body weight gain in the non-diabetic animals. Interestingly, the impaired neuronal function in diabetic animals could be prevented by glucosamine treatment. Correspondingly, the activation of Müller cells was prevented in the retina as well as in cell culture. Conversely, glucosamine administration in the normal retina damaged the retinal vasculature by increasing pericyte loss and acellular capillary formation, likely by interfering with endothelial survival signals as seen in vitro in cultured endothelial cells. Nevertheless, under diabetic conditions, no further increase in the detrimental effects were observed. Conclusions In conclusion, the effects of glucosamine supplementation in the retina appear to be a double-edged sword: neuronal protection in the diabetic retina and vascular damage in the normal retina. Thus, glucosamine supplementation in osteoarthritis patients with or without diabetes should be taken with care.
Ablation of nucleoside diphosphate kinase B (NDPK-B) in mice causes a breakdown of the neurovascular unit in the retina, mimicking diabetic retinopathy. The NDPK-B deficiency-induced vascular damage is mediated by excessive angiopoietin 2 (Ang2). Herein, the potential involvement of its receptor, Tie2, was investigated. NDPK-B-deficient mouse retinas showed an upregulation of Tie2, specifically in the deep capillary layer. A similar upregulation of Tie2 was observed in cultured endothelial cells (ECs) from different origins upon NDPK-B depletion, whereas high glucose (HG) treatment did not alter Tie2 expression. Immunofluorescence staining and subcellular fractionation showed that the majority of Tie2 upregulation occurred at the plasma membrane. Similar to HG, however, NDPK-B depletion reduced Tie2 tyrosine phosphorylation. Compared to HG, a stronger increase of Ang2 was observed in NDPK-B depleted ECs. Treatment of ECs with soluble Tie2 or siRNA-mediated Tie2 knockdown attenuated NDPK-B depletion- but not HG-induced Ang2 upregulation. Like NDPK-B depletion, overexpression of recombinant Ang2 in ECs enhanced Ang2 secretion and concomitantly promoted the upregulation of Tie2. Thus, we identified a new mechanism showing that after reaching a threshold level of secretion, Ang2 sustains its own expression and secretion by a Tie2-dependent positive feedback loop.
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