Tissues with high metabolic rates often use lipid as well as glucose for energy, conferring a survival advantage during feast and famine.1 Current dogma suggests that high-energy consuming photoreceptors depend on glucose.2,3 Here we show that retina also uses fatty acids (FA) β-oxidation for energy. Moreover, we identify a lipid sensor Ffar1 that curbs glucose uptake when FA are available. Very low-density lipoprotein receptor (VLDLR), expressed in tissues with a high metabolic rate, facilitates the uptake of triglyceride-derived FA.4,5 Vldlr is present in photoreceptors.6 In Vldlr−/− retinas, Ffar1, sensing high circulating lipid levels despite decreased FA uptake5, suppresses glucose transporter Glut1. This impaired glucose entry into photoreceptors results in a dual lipid/glucose fuel shortage and reduction in the Krebs cycle intermediate α-ketoglutarate (KG). Low α-KG levels promote hypoxia-induced factor-1α (Hif1a) stabilization and vascular endothelial growth factor (Vegfa) secretion by starved Vldlr−/− photoreceptors, attracting neovessels to supply fuel. These aberrant vessels invading normally avascular photoreceptors in Vldlr−/− retinas are reminiscent of retinal angiomatous proliferation (RAP), a subset of neovascular age-related macular degeneration (AMD)7, associated with high vitreous VEGF levels in humans. Dysregulated lipid and glucose photoreceptor energy metabolism may therefore be a driving force in neovascular AMD and other retinal diseases.

SummaryStem cell therapy for retinal disease is under way, and several clinical trials are currently recruiting. These trials use human embryonic, foetal and umbilical cord tissue-derived stem cells and bone marrow-derived stem cells to treat visual disorders such as age-related macular degeneration, Stargardt's disease and retinitis pigmentosa. Over a decade of analysing the developmental cues involved in retinal generation and stem cell biology, coupled with extensive surgical research, have yielded differing cellular approaches to tackle these retinopathies. Here, we review these various stem cell-based approaches for treating retinal diseases and discuss future directions and challenges for the field.

PURPOSE To assess the histopathological changes in a postmortem sample derived from an eye donor with Macular Telangiectasia Type 2 (MacTel type 2) to gain further insight into the cause of the disease. DESIGN Clinicopathological case report PARTICIPANTS Postmortem tissue was collected from 5 different donors: one MacTel type 2 patient, one healthy control, two type 2 diabetic patients; one with retinopathy and one without retinopathy, and one patient with unilateral Coat’s disease. METHODS Macular pigment distribution in the posterior part of freshly dissected eyes was documented by macro photography. Paraffin sections from both the macular and peripheral regions were assessed using antigen retrieval and immunohistochemistry to study the distribution of cell-specific markers. Blood vessels were visualized with antibodies directed against collagen IV and claudin5, glial cells with antibodies against glial fibrillary acidic protein (GFAP), vimentin, glutamine synthetase (GS) and retinaldehyde binding protein (RLBP1, also known as CRALBP), microglia with an antibody against allograft inflammatory factor 1 (AIF1, also known as Iba1) and photoreceptors with antibodies against rhodopsin and opsin. Using anatomical landmarks the sections were then matched with the macular pigment distribution and a fluorescein angiogram of the patient that was taken before the patient’s death. MAIN OUTCOME MEASURES Presence and distribution of macular pigment and cell-specific markers. RESULTS Macular pigment was absent in the macula. Furthermore, abnormally dilated capillaries were identified in a macular region that correlated spatially with regions of fluorescein leakage in an angiogram that was taken 12 years prior to death. These telangiectatic vessels displayed a marked reduction of the basement membrane component collagen IV, indicating vascular pathology. GFAP was limited to retinal astrocytes and no reactive Müller cells were identified. Importantly, reduced immunoreactivity with Müller cell markers (vimentin, GS and RLBP1) in the macula was observed. The area that lacked Müller cells corresponded with the region of depleted macular pigment. CONCLUSIONS These findings suggest that macular Müller cell loss or dysfunction is a critical component of MacTel type 2, which may have implications for future treatment strategies.

We have confirmed our previous finding of Müller's cell loss in MacTel type 2 and have shown that the area of Müller's cell loss matches the area of macular pigment depletion. In this patient, the IS/OS junction seen by OCT was absent in a region where rods were depleted but cones were still present.

PURPOSE.To investigate the impact of diabetic macular ischemia (DMI) on visual acuity (VA), through the analysis of novel fluorescein angiography (FA) parameters.METHODS. Data were retrospectively collected over a 6-month period. DMI severity was graded using Early Treatment Diabetic Retinopathy Study (ETDRS) protocols. Custom software was used to quantify areas of the foveal avascular zone (FAZ), and of capillary nonperfusion over the papillomacular nerve fiber layer bundle, and temporal macula, and associations tested with VA. RESULTS.A total of 488 patients with type 2 diabetes mellitus and FAs of sufficient quality to allow detailed quantitative analyses were included. ETDRS-DMI severity was graded as: none, 39.7%; questionable, 18.4%; mild, 25.2%; moderate, 11.0%; and severe, 5.6%. Median FAZ areas were 0.19 mm CONCLUSIONS. Diabetic macular ischemia is associated with reduced VA in eyes with moderate to severe ETDRS-DMI grades of ischemia but preserved in milder grades. In addition, we describe the independent association of papillomacular nerve fiber bundle ischemia with reduced VA. (Invest Ophthalmol Vis Sci.