Relevance of Peptide Homeostasis in Metabolic Retinal Degenerative Disorders: Curative Potential in Genetically Modified Mice

The mammalian retina contains approximately 30 neuropeptides that are synthetized by different neuronal cell populations, glia, and the pigmented epithelium. The presence of these neuropeptides leaves a mark on normal retinal molecular processes and physiology, and they are also crucial in fighting various pathologies (e.g., diabetic retinopathy, ischemia, age-related pathologies, glaucoma) because of their protective abilities. Retinal pathologies of different origin (metabolic, genetic) are extensively investigated by genetically manipulated in vivo mouse models that help us gain a better understanding of the molecular background of these pathomechanisms. These models offer opportunities to manipulate gene expression in different cell types to help reveal their roles in the preservation of retinal health or identify malfunction during diseases. In order to assess the current status of transgenic technologies available, we have conducted a literature survey focused on retinal disorders of metabolic origin, zooming in on the role of retinal neuropeptides in diabetic retinopathy and ischemia. First, we identified those neuropeptides that are most relevant to retinal pathologies in humans and the two clinically most relevant models, mice and rats. Then we continued our analysis with metabolic disorders, examining neuropeptide-related pathways leading to systemic or cellular damage and rescue. Last but not least, we reviewed the available literature on genetically modified mouse strains to understand how the manipulation of a single element of any given pathway (e.g., signal molecules, receptors, intracellular signaling pathways) could lead either to the worsening of disease conditions or, more frequently, to substantial improvements in retinal health. Most attention was given to studies which reported successful intervention against specific disorders. For these experiments, a detailed evaluation will be given and the possible role of converging intracellular pathways will be discussed. Using these converging intracellular pathways, curative effects of peptides could potentially be utilized in fighting metabolic retinal disorders.

Expression of Otx Genes in Müller Cells Using an In Vitro Experimental Model of Retinal Hypoxia

Introduction. Müller glial cells typically activate to react to hypoxic tissue damage in several retinal diseases. We evaluated the in vitro response to a hypoxia-mimicking stimulus on the expression of a set of genes, known to contribute to eye morphogenesis and cell differentiation. Materials and Methods. A MIO-M1 Müller cell line was cultured in a hypoxia-mimicking environment by the addition of cobalt chloride to the culture medium, followed by a recovery time in which we mimic restoration from the hypoxic insult. The HIF-1α protein and VEGF-A gene expression were quantified to verify the induction of a hypoxia-like state. Results. Among the genes under study, we did not observe any difference in the expression levels of Otx1 and Otx2 during treatment; conversely, Otx1 was overexpressed during recovery steps. The VEGF-A gene was strongly upregulated at both the CoCl2 and recovery time points. The transactivated isoform (TA) of the TP73 gene showed an overexpression in long-term exposure to the hypoxic stimulus with a further increase after recovery. Discussion. Our molecular analysis is able to describe the activation of a set of genes, never before described, that can drive the response to a hypoxia-like status. The improved comprehension of these cellular events will be useful for designing new therapeutical approaches for retinal pathologies.

Vitrectomy in Congenital Vitreous Pathologies

Congenital vitreous diseases are the result of embryological development defects of the vitreous. These diseases have a wide spectrum including congenital vitreous disorders and genetically impaired vitreous structure. Also, these diseases are the first diseases that should come to mind in vitreous and retinal pathologies seen in the early age group. In many of them, pars plana vitrectomy has an important role in the treatment. Due to the disease pathophysiology and age of the patients, they differ from the standard pars plana vitrectomy. In this review, congenital vitreous pathologies and the vitrectomy method applied in the treatment of these pathologies will be discussed.

Simultaneous visible light optical coherence tomography and near infrared OCT angiography in retinal pathologies: A case study

A dual-channel optical coherence tomography system with wavelengths in the visible and near-infrared light ranges can provide both structural and functional information for retinal microvasculature simultaneously. We applied this integrated system in an ongoing clinical study of patients with various retinal pathologies. Here, we present case study results of patients with diabetic retinopathy, central retinal vein occlusion, and sickle cell retinopathy compared to a healthy subject. For the first time, this comparison validates the system’s ability to detect structural anomalies in both en face and B-scan images with simultaneous retinal optical coherence tomography angiography and measurement of sO2 in parafoveal vessels that are around 20–30 µm in diameter. This integrated system represents a powerful instrument with potentially far-reaching clinical implications for the early detection and diagnosis of retinal vascular diseases.

Functionally Assessing the Age-Related Decline in the Detection Rate of Photons by Cone Photoreceptors

Age-related decline in visual perception is usually attributed to optical factors of the eye and neural factors. However, the detection of light by cones converting light into neural signals is a crucial intermediate processing step of vision. Interestingly, a novel functional approach can evaluate many aspects of the visual system including the detection of photons by cones. This approach was used to investigate the underlying cause of age-related visual decline and found that the detection rate of cones was considerably affected with healthy aging. This functional test enabling to evaluate the detection of photons by cones could be particularly useful to screen for retinal pathologies affecting cones such as age-related macular degeneration. However, the paradigm used to functionally measure the detection of photons was complex as it was evaluating many other properties of the visual system. The aim of the current mini review is to clarify the underlying rationale of functionally evaluating the detection of photons by cones, describe a simpler approach to evaluate it, and review the impact of aging on the detection rate of cones.

Differential Responses of Neural Retina Progenitor Populations to Chronic Hyperglycemia

Diabetic retinopathy is a frequent complication of longstanding diabetes, which comprises a complex interplay of microvascular abnormalities and neurodegeneration. Zebrafish harboring a homozygous mutation in the pancreatic transcription factor pdx1 display a diabetic phenotype with survival into adulthood, and are therefore uniquely suitable among zebrafish models for studying pathologies associated with persistent diabetic conditions. We have previously shown that, starting at three months of age, pdx1 mutants exhibit not only vascular but also neuro-retinal pathologies manifesting as photoreceptor dysfunction and loss, similar to human diabetic retinopathy. Here, we further characterize injury and regenerative responses and examine the effects on progenitor cell populations. Consistent with a negative impact of hyperglycemia on neurogenesis, stem cells of the ciliary marginal zone show an exacerbation of aging-related proliferative decline. In contrast to the robust Müller glial cell proliferation seen following acute retinal injury, the pdx1 mutant shows replenishment of both rod and cone photoreceptors from slow-cycling, neurod-expressing progenitors which first accumulate in the inner nuclear layer. Overall, we demonstrate a diabetic retinopathy model which shows pathological features of the human disease evolving alongside an ongoing restorative process that replaces lost photoreceptors, at the same time suggesting an unappreciated phenotypic continuum between multipotent and photoreceptor-committed progenitors.

Risk factors for microcystic macular oedema in glaucoma

Background/aimsTo identify clinical characteristics and factors associated with microcystic macular edema (MME) in patients with primary open-angle glaucoma (POAG).MethodsWe included 315 POAG eyes between 2010 and 2019 with good-quality macular volume scans that had reliable visual fields (VF) available within 6 months in this observational retrospective cohort study. Eyes with retinal pathologies except for epiretinal membrane (ERM) were excluded. The inner nuclear layer was qualitatively assessed for the presence of MME. Global mean deviation (MD) and Visual Field Index (VFI) decay rates, superior and inferior MD rates and pointwise total deviation rates of change were estimated with linear regression. Logistic regression was performed to identify baseline factors associated with the presence of MME and to determine whether MME is associated with progressive VF loss.Results25 out of 315 eyes (7.9%) demonstrated MME. The average (±SD) age and MD in eyes with and without MME was 57.2 (±8.7) versus 62.0 (±9.9) years (p=0.02) and −9.8 (±5.7) versus −4.9 (±5.3) dB (p<0.001), respectively. Worse global MD at baseline (p=0.001) and younger age (p=0.02) were associated with presence of MME. ERM was not associated with the presence of MME (p=0.84) in this cohort. MME was not associated with MD and VFI decay rates (p>0.49).ConclusionsMore severe glaucoma and younger age were associated with MME. MME was not associated with faster global VF decay in this cohort. MME may confound monitoring of glaucoma with full macular thickness.

SARS-CoV-2 infects and replicates in photoreceptor and retinal ganglion cells of human retinal organoids

Several studies have pointed to retinal involvement in COVID 19 disease, yet many questions remain regarding the ability of SARS CoV 2 to infect and replicate in retinal cells and its effects on the retina. Here we have used human stem cell derived retinal organoids to study retinal infection by the SARS CoV 2 virus. Indeed, SARS CoV 2 can infect and replicate in retinal organoids, as it is shown to infect different retinal lineages, such as retinal ganglion cells and photoreceptors. SARS CoV 2 infection of retinal organoids also induces the expression of several inflammatory genes, such as interleukin 33, a gene associated with acute COVID 19 disease and retinal degeneration. Finally, we show that the use of antibodies to block the ACE2 receptor significantly reduces SARS CoV 2 infection of retinal organoids, indicating that SARS CoV 2 infects retinal cells in an ACE2 dependent manner. These results suggest a retinal involvement in COVID 19 and emphasize the need to monitor retinal pathologies as potential sequelae of long COVID.