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Medecine Sciences : M/S 2020The neuroretina is a functional unit of the central nervous system that converts a light signal into a nerve impulse. Of neuroectodermal origin, derived from the... (Review)
Review
The neuroretina is a functional unit of the central nervous system that converts a light signal into a nerve impulse. Of neuroectodermal origin, derived from the diencephalon, the neuroretina is a layered tissue composed of six types of neuronal cells (two types of photoreceptors: cones and rods, horizontal, bipolar, amacrine and ganglion cells) and three types of glial cells (Müller glial cells, astrocytes and microglial cells). The neuroretina lays on the retinal pigmentary epithelium, that together form the retina. The existence of the internal and external blood-retinal barriers and intra-retinal junctions reflects the fineness of regulation of the retinal exchanges with the circulation and within the retina itself. The central zone of the human retina, which is highly specialized for visual acuity, has anatomical specificities. Recent imaging methods make it possible now to enrich our knowledge of the anatomical and functional characteristics of the retina, which are still imperfectly described.
Topics: Animals; Choroid; Humans; Neuroglia; Retina; Retinal Cone Photoreceptor Cells; Retinal Pigment Epithelium; Retinal Rod Photoreceptor Cells; Retinal Vessels
PubMed: 32614310
DOI: 10.1051/medsci/2020094 -
Current Opinion in Ophthalmology Mar 2022Biomechanics is an important aspect of the complex family of diseases known as the glaucomas. Here, we review recent studies of biomechanics in glaucoma. (Review)
Review
PURPOSE OF REVIEW
Biomechanics is an important aspect of the complex family of diseases known as the glaucomas. Here, we review recent studies of biomechanics in glaucoma.
RECENT FINDINGS
Several tissues have direct and/or indirect biomechanical roles in various forms of glaucoma, including the trabecular meshwork, cornea, peripapillary sclera, optic nerve head/sheath, and iris. Multiple mechanosensory mechanisms and signaling pathways continue to be identified in both the trabecular meshwork and optic nerve head. Further, the recent literature describes a variety of approaches for investigating the role of tissue biomechanics as a risk factor for glaucoma, including pathological stiffening of the trabecular meshwork, peripapillary scleral structural changes, and remodeling of the optic nerve head. Finally, there have been advances in incorporating biomechanical information in glaucoma prognoses, including corneal biomechanical parameters and iridial mechanical properties in angle-closure glaucoma.
SUMMARY
Biomechanics remains an active aspect of glaucoma research, with activity in both basic science and clinical translation. However, the role of biomechanics in glaucoma remains incompletely understood. Therefore, further studies are indicated to identify novel therapeutic approaches that leverage biomechanics. Importantly, clinical translation of appropriate assays of tissue biomechanical properties in glaucoma is also needed.
Topics: Biomechanical Phenomena; Glaucoma; Humans; Intraocular Pressure; Optic Disk; Sclera; Trabecular Meshwork
PubMed: 34954731
DOI: 10.1097/ICU.0000000000000829 -
Annual Review of Vision Science Sep 2021The outer retina is nourished from the choroid, a capillary bed just inside the sclera. O, glucose, and other nutrients diffuse out of the choroid and then filter... (Review)
Review
The outer retina is nourished from the choroid, a capillary bed just inside the sclera. O, glucose, and other nutrients diffuse out of the choroid and then filter through a monolayer of retinal pigment epithelium (RPE) cells to fuel the retina. Recent studies of energy metabolism have revealed striking differences between retinas and RPE cells in the ways that they extract energy from fuels. The purpose of this review is to suggest and evaluate the hypothesis that the retina and RPE have complementary metabolic roles that make them depend on each other for survival and for their abilities to perform essential and specialized functions.
Topics: Choroid; Energy Metabolism; Retina; Retinal Pigment Epithelium
PubMed: 34102066
DOI: 10.1146/annurev-vision-100419-115156 -
Nature Mar 2022Interoception, the ability to timely and precisely sense changes inside the body, is critical for survival. Vagal sensory neurons (VSNs) form an important body-to-brain...
Interoception, the ability to timely and precisely sense changes inside the body, is critical for survival. Vagal sensory neurons (VSNs) form an important body-to-brain connection, navigating visceral organs along the rostral-caudal axis of the body and crossing the surface-lumen axis of organs into appropriate tissue layers. The brain can discriminate numerous body signals through VSNs, but the underlying coding strategy remains poorly understood. Here we show that VSNs code visceral organ, tissue layer and stimulus modality-three key features of an interoceptive signal-in different dimensions. Large-scale single-cell profiling of VSNs from seven major organs in mice using multiplexed projection barcodes reveals a 'visceral organ' dimension composed of differentially expressed gene modules that code organs along the body's rostral-caudal axis. We discover another 'tissue layer' dimension with gene modules that code the locations of VSN endings along the surface-lumen axis of organs. Using calcium-imaging-guided spatial transcriptomics, we show that VSNs are organized into functional units to sense similar stimuli across organs and tissue layers; this constitutes a third 'stimulus modality' dimension. The three independent feature-coding dimensions together specify many parallel VSN pathways in a combinatorial manner and facilitate the complex projection of VSNs in the brainstem. Our study highlights a multidimensional coding architecture of the mammalian vagal interoceptive system for effective signal communication.
Topics: Animals; Brain; Calcium; Mammals; Mice; Perception; Psychophysiology; Sensory Receptor Cells; Vagus Nerve; Vomeronasal Organ
PubMed: 35296859
DOI: 10.1038/s41586-022-04515-5 -
International Journal of Molecular... Jun 2017Dry eye can damage the ocular surface and result in mild corneal epithelial defect to blinding corneal pannus formation and squamous metaplasia. Significant progress in... (Review)
Review
Dry eye can damage the ocular surface and result in mild corneal epithelial defect to blinding corneal pannus formation and squamous metaplasia. Significant progress in the treatment of dry eye has been made in the last two decades; progressing from lubricating and hydrating the ocular surface with artificial tear to stimulating tear secretion; anti-inflammation and immune regulation. With the increase in knowledge regarding the pathophysiology of dry eye, we propose in this review the concept of ocular surface microenvironment. Various components of the microenvironment contribute to the homeostasis of ocular surface. Compromise in one or more components can result in homeostasis disruption of ocular surface leading to dry eye disease. Complete evaluation of the microenvironment component changes in dry eye patients will not only lead to appropriate diagnosis, but also guide in timely and effective clinical management. Successful treatment of dry eye should be aimed to restore the homeostasis of the ocular surface microenvironment.
Topics: Cellular Microenvironment; Conjunctiva; Cornea; Dry Eye Syndromes; Eye; Eyelids; Homeostasis; Hormones; Humans; Lacrimal Apparatus; Lubricant Eye Drops; Meibomian Glands; Microbiota; Tears
PubMed: 28661456
DOI: 10.3390/ijms18071398 -
Progress in Retinal and Eye Research Jul 2021Diabetic retinopathy (DR) is a leading cause of blindness. It has long been regarded as vascular disease, but work in the past years has shown abnormalities also in the... (Review)
Review
Diabetic retinopathy (DR) is a leading cause of blindness. It has long been regarded as vascular disease, but work in the past years has shown abnormalities also in the neural retina. Unfortunately, research on the vascular and neural abnormalities have remained largely separate, instead of being integrated into a comprehensive view of DR that includes both the neural and vascular components. Recent evidence suggests that the most predominant neural cell in the retina (photoreceptors) and the adjacent retinal pigment epithelium (RPE) play an important role in the development of vascular lesions characteristic of DR. This review summarizes evidence that the outer retina is altered in diabetes, and that photoreceptors and RPE contribute to retinal vascular alterations in the early stages of the retinopathy. The possible molecular mechanisms by which cells of the outer retina might contribute to retinal vascular damage in diabetes also are discussed. Diabetes-induced alterations in the outer retina represent a novel therapeutic target to inhibit DR.
Topics: Diabetes Mellitus; Diabetic Retinopathy; Humans; Photoreceptor Cells; Retina; Retinal Pigment Epithelium
PubMed: 33188897
DOI: 10.1016/j.preteyeres.2020.100919 -
The Ocular Surface Jul 2021Single cell (sc) analyses of key embryonic, fetal and adult stages were performed to generate a comprehensive single cell atlas of all the corneal and adjacent...
PURPOSE
Single cell (sc) analyses of key embryonic, fetal and adult stages were performed to generate a comprehensive single cell atlas of all the corneal and adjacent conjunctival cell types from development to adulthood.
METHODS
Four human adult and seventeen embryonic and fetal corneas from 10 to 21 post conception week (PCW) specimens were dissociated to single cells and subjected to scRNA- and/or ATAC-Seq using the 10x Genomics platform. These were embedded using Uniform Manifold Approximation and Projection (UMAP) and clustered using Seurat graph-based clustering. Cluster identification was performed based on marker gene expression, bioinformatic data mining and immunofluorescence (IF) analysis. RNA interference, IF, colony forming efficiency and clonal assays were performed on cultured limbal epithelial cells (LECs).
RESULTS
scRNA-Seq analysis of 21,343 cells from four adult human corneas and adjacent conjunctivas revealed the presence of 21 cell clusters, representing the progenitor and differentiated cells in all layers of cornea and conjunctiva as well as immune cells, melanocytes, fibroblasts, and blood/lymphatic vessels. A small cell cluster with high expression of limbal progenitor cell (LPC) markers was identified and shown via pseudotime analysis to give rise to five other cell types representing all the subtypes of differentiated limbal and corneal epithelial cells. A novel putative LPCs surface marker, GPHA2, expressed on the surface of 0.41% ± 0.21 of the cultured LECs, was identified, based on predominant expression in the limbal crypts of adult and developing cornea and RNAi validation in cultured LECs. Combining scRNA- and ATAC-Seq analyses, we identified multiple upstream regulators for LPCs and demonstrated a close interaction between the immune cells and limbal progenitor cells. RNA-Seq analysis indicated the loss of GPHA2 expression and acquisition of proliferative limbal basal epithelial cell markers during ex vivo LEC expansion, independently of the culture method used. Extending the single cell analyses to keratoconus, we were able to reveal activation of collagenase in the corneal stroma and a reduced pool of limbal suprabasal cells as two key changes underlying the disease phenotype. Single cell RNA-Seq of 89,897 cells obtained from embryonic and fetal cornea indicated that during development, the conjunctival epithelium is the first to be specified from the ocular surface epithelium, followed by the corneal epithelium and the establishment of LPCs, which predate the formation of limbal niche by a few weeks.
CONCLUSIONS
Our scRNA-and ATAC-Seq data of developing and adult cornea in steady state and disease conditions provide a unique resource for defining genes/pathways that can lead to improvement in ex vivo LPCs expansion, stem cell differentiation methods and better understanding and treatment of ocular surface disorders.
Topics: Adult; Cell Differentiation; Cells, Cultured; Cornea; Epithelial Cells; Epithelium, Corneal; Humans; Limbus Corneae; Stem Cells
PubMed: 33865984
DOI: 10.1016/j.jtos.2021.03.010 -
Proceedings of the National Academy of... Nov 2019The human retinal pigment epithelium (RPE) and choroid are complex tissues that provide crucial support to the retina. Disease affecting either of these supportive...
The human retinal pigment epithelium (RPE) and choroid are complex tissues that provide crucial support to the retina. Disease affecting either of these supportive tissues can lead to irreversible blindness in the setting of age-related macular degeneration. In this study, single-cell RNA sequencing was performed on macular and peripheral regions of RPE-choroid from 7 human donor eyes in 2 independent experiments. In the first experiment, total RPE/choroid preparations were evaluated and expression profiles specific to RPE and major choroidal cell populations were identified. As choroidal endothelial cells represent a minority of the total RPE/choroidal cell population but are strongly implicated in age-related macular degeneration (AMD) pathogenesis, a second single-cell RNA-sequencing experiment was performed using endothelial cells enriched by magnetic separation. In this second study, we identified gene expression signatures along the choroidal vascular tree, classifying the transcriptome of human choriocapillaris, arterial, and venous endothelial cells. We found that the choriocapillaris highly and specifically expresses the regulator of cell cycle gene (), a gene that responds to complement activation and induces apoptosis in endothelial cells. In addition, was the most up-regulated choriocapillaris gene in a donor diagnosed with AMD. These results provide a characterization of the human RPE and choriocapillaris transcriptome, offering potential insight into the mechanisms of choriocapillaris response to complement injury and choroidal vascular disease in age-related macular degeneration.
Topics: Choroid; Epithelial Cells; Epithelium; Humans; Macular Degeneration; Retina; Single-Cell Analysis; Transcriptome
PubMed: 31712411
DOI: 10.1073/pnas.1914143116 -
Progress in Retinal and Eye Research Jul 2021Gene expression provides valuable insight into cell function. As such, vision researchers have frequently employed gene expression studies to better understand retinal... (Review)
Review
Gene expression provides valuable insight into cell function. As such, vision researchers have frequently employed gene expression studies to better understand retinal physiology and disease. With the advent of single-cell RNA sequencing, expression experiments provide an unparalleled resolution of information. Instead of studying aggregated gene expression across all cells in a heterogenous tissue, single-cell technology maps RNA to an individual cell, which facilitates grouping of retinal and choroidal cell types for further study. Single-cell RNA sequencing has been quickly adopted by both basic and translational vision researchers, and single-cell level gene expression has been studied in the visual systems of animal models, retinal organoids, and primary human retina, RPE, and choroid. These experiments have generated detailed atlases of gene expression and identified new retinal cell types. Likewise, single-cell RNA sequencing investigations have characterized how gene expression changes in the setting of many retinal diseases, including how choroidal endothelial cells are altered in age-related macular degeneration. In addition, this technology has allowed vision researchers to discover drivers of retinal development and model rare retinal diseases with induced pluripotent stem cells. In this review, we will overview the growing number of single-cell RNA sequencing studies in the field of vision research. We will summarize experimental considerations for designing single-cell RNA sequencing experiments and highlight important advancements in retinal, RPE, choroidal, and retinal organoid biology driven by this technology. Finally, we generalize these findings to genes involved in retinal degeneration and outline the future of single-cell expression experiments in studying retinal disease.
Topics: Animals; Choroid; Endothelial Cells; Humans; Retina; Retinal Degeneration; Retinal Pigment Epithelium; Sequence Analysis, RNA
PubMed: 33383180
DOI: 10.1016/j.preteyeres.2020.100934 -
American Journal of Human Genetics Jun 2022Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss... (Meta-Analysis)
Meta-Analysis
Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss.
Topics: Animals; Cochlea; Deafness; Genome-Wide Association Study; Hearing Loss; Humans; Mice; Stria Vascularis
PubMed: 35580588
DOI: 10.1016/j.ajhg.2022.04.010