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Transplantation of retinal progenitor cells from optic cup-like structures differentiated from human embryonic stem cells in vitro and in vivo generation of retinal ganglion-like cells
摘要： Human embryonic stem cells (hESCs) have the potential to differentiate along the retinal lineage. We have efficiently differentiated human pluripotent stem cells (hPSCs) into optic cup-like structures by using a novel retinal differentiation medium (RDM).The purpose of this study was to determine whether the retinal progenitor cells (RPCs) derived from hESCs can integrate into the host retina and differentiate into retinal ganglion cells (RGCs) in vivo. In the present study, hESCs (H9-GFP) were induced to differentiate into optic cup-like structures by using our novel differentiation system. The RPCs extracted from the optic cup-like structures were transplanted into the vitreous cavity of N-Methyl-D-aspartic acid (NMDA)-treated mice. Sham-treated eyes received the same amount of retinal differentiation medium (RDM). The host retinas were analyzed by triple immunofluorescence on the 4th and 5th weeks after transplantation. The optic cup-like structures were efficiently differentiated from hESCs by using our novel differentiation system in vitro for 6-8 weeks. The RPCs extracted from the optic cup-like structures migrated and integrated into the GCL of the host retina. Furthermore, the remaining transplanted cells were spread over the GCL and had a complementary distribution with host residual RGCs in the GCL of the mouse retina. Surprisingly, some of the transplanted cells expressed the RGC-specific marker Brn3a. These findings demonstrated that the RPCs derived from hESCs could integrate into the host GCL and differentiate into retinal ganglion-like cells in vivo, suggesting that RPCs can be used as an ideal source in supplying countless RGC and ESC-based replacement therapies may be a promising treatment to restore vision in patients with degenerative retinal diseases.
关键词： retinal ganglion cells,human embryonic stem cells,transplantation,optic cup-like structures,retinal progenitor cells
更新于2025-09-04 15:30:14
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Macular Inner Retinal Layer Thickness in Relation to Photopic and Mesopic Contrast Sensitivity in Healthy Young and Older Subjects
摘要： PURPOSE. To examine relationships between the thicknesses of ganglion cell (GC)-related macular layers and central photopic or mesopic contrast sensitivity (CS) in healthy eyes. METHODS. Measurements were made in 38 young and 38 older healthy individuals. Total, inner, layer (IRL) thicknesses were measured in the macula region through and outer retinal spectral-domain optical coherence tomography (SD-OCT) across three sub?elds, or rings, centered at the fovea: central foveal, pericentral, and peripheral. Ganglion cell complex and circumpapillary retinal nerve ?ber layer thicknesses were also measured. Low-spatial-frequency CS for gratings presented at the central 108 visual ?eld were measured through computerized psychophysical tests under photopic and mesopic conditions. Relationships were examined by uni- and multivariate regression analysis. RESULTS. Peripheral IRL thickness emerged as the only independent predictor of photopic CS (P ? 0.001) in the young group and of photopic (P ? 0.026) and mesopic CS (P ? 0.001) in the older group. The slopes of regression lines used to predict CS from peripheral IRL thickness were signi?cantly different for pair-wise comparisons of both photopic CS and age group (P ? 0.0001) and mesopic CS (P ? 0.0001) and age group. These models explained 37% of the variability in photopic CS and 36% of the variability in mesopic CS. CONCLUSIONS. Macular IRL thinning likely due to GC loss was related to reduced photopic and mesopic CS in older healthy eyes. In contrast, in the young eyes, a thicker macular IRL, possibly indicating transient gliosis, was associated with reduced CS.
关键词： contrast sensitivity,optical coherence tomography,retinal ganglion cells,macular inner retinal layer thickness,mesopic vision,glial cells
更新于2025-09-04 15:30:14
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Optic nerve head width and retinal nerve fiber layer changes are good indexes for validating the successful induction of experimental anterior ischemic optic neuropathy
摘要： Reproducible skills are essential for successful induction of a rat model of anterior ischemic optic neuropathy (rAION). We established an in vivo validation index by measuring the natural course of optic nerve head (ONH) width and retinal nerve fiber layer (RNFL) thickness in the rAION model using optical coherence tomography (OCT). The rAION model was induced by photodynamic operations. We measured the ONH width and RNFL thickness in the acute stage (<3 days), subacute stage (day 7 and day 14) and later stage (day 28) post-infarct by OCT. RNFL were measured by hematoxylin and eosin stain (HE) to confirm the OCT findings. The RGCs survival rate was determined by retrograde Fluoro-gold labeling, and the visual function was assessed with flash visual-evoked potentials (FVEPs) 4 weeks post-infarct. The ONH showed significant swelling in the acute stage, which also correlated with RNFL swelling. The swelling was reduced to normal within one-week post-infarct. The rAION group (0.51± 0.12 mm2) showed a significant RNFL thinning when compared with sham groups (0.92±0.15 mm2, p<0.05) on day-28 post-infarct. And HE-stained retina cross sections also showed RNFL thinning, which further confirmed our OCT Findings. The RGC density and P1-N2 amplitude were significantly reduced in rAION. Swelling, reduction of swelling, and atrophy of RNFL in acute, sub-acute, and later stage, respectively, are important events for confirming the successful induction of rAION. They suggest that the longitudinal OCT data provides a reliable index for validating the reproducibility and correct order of rAION.
关键词： optic nerve head (ONH),retinal ganglion cells (RGCs),optical coherence tomography (OCT),anterior ischemic optic neuropathy in rats (rAION),retina nerve fiber layer (RNFL)
更新于2025-09-04 15:30:14
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Influence of <i>Opa1</i> Mutation on Survival and Function of Retinal Ganglion Cells
摘要： PURPOSE. Mutations in the OPA1 gene cause autosomal dominant optic atrophy (ADOA), a visual disorder associated with degeneration of retinal ganglion cells (RGCs). Here, we characterized the disease progression in a homologous mouse model B6;C3-Opa1329-355del and asked whether the pronounced cell death affects certain RGC types more than others. METHODS. The in?uence of the Opa1 mutation was assessed by morphologic (retina and optic nerve histology) and functional (multielectrode array) methods. RESULTS. The RGC loss of approximately 50% within 18 months was signi?cantly more pronounced in RGCs with small-caliber axons. Small-caliber axon RGCs comprise a variety of functional RGC types. Accordingly, electrophysiological analyses of RGCs did not show a dropout of distinct functional RGC subgroups. However, the response properties of RGCs were affected signi?cantly by the mutation. Surprisingly, these functional changes were different under different luminance conditions (scotopic, mesopic, and photopic). Finally, melanopsin cells are known to be less susceptible to retinal insults. We found that these cells are also spared in the Opa1 mouse model, and demonstrated for the ?rst time that this resistance persisted even when the melanopsin gene had been knocked-out. CONCLUSIONS. Small-caliber axons show a higher vulnerability to the Opa1 mutation in our mouse model for ADOA. Luminance-dependent functional changes suggest an in?uence of the Opa1 mutation on the retinal circuitry upstream of RGCs. Photoresponsive RGCs are protected against cell death due to the Opa1 mutation, but not by melanopsin expression itself.
关键词： retinal ganglion cells,optic nerve,melanopsin,MEA recordings,optic neuropathy
更新于2025-09-04 15:30:14
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Spatiotemporal Expression Changes of PACAP and Its Receptors in Retinal Ganglion Cells After Optic Nerve Crush
摘要： Pituitary adenylate cyclase-activating polypeptide (PACAP) has been demonstrated to play a crucial part in protecting retinal ganglion cells (RGCs) from apoptosis in various retinal injury animal models. PACAP has two basic groups of receptors: PACAP receptor type 1 (PAC1R) and vasoactive intestinal polypeptide/PACAP receptors (VPAC1R and VPAC2R). However, few studies illustrated the spatial and temporal expression changes of endogenous PACAP and its receptors in a rodent optic nerve crush (ONC) model. In this study, a significant upregulation of PACAP and PAC1R in the retina after ONC was observed in both protein and RNA levels. The peak level of PACAP and PAC1R expression could be found on the fifth day following ONC. In addition, immunofluorescent labeling indicated that PACAP and PAC1R were localized mainly in RGCs. On the contrary, VPAC1R and VPAC2R were hardly detected in the retina. Collectively, the spatiotemporal expression of PACAP and its high-affinity receptor PAC1R were remarkably changed after ONC, and mainly expressed in the ganglion cell layer of the retina. This suggested that the upregulation of PACAP and PAC1R may play a vital role in RGC death after ONC.
关键词： PACAP,Receptors,Rat,Retinal ganglion cells,Optic nerve crush
更新于2025-09-04 15:30:14
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The Role of Endogenous Neuroprotective Mechanisms in the Prevention of Retinal Ganglion Cells Degeneration
摘要： Retinal neurons are not able to undergo spontaneous regeneration in response to damage. A variety of stressors, i.e., UV radiation, high temperature, ischemia, allergens, and others, induce reactive oxygen species production, resulting in consecutive alteration of stress-response gene expression and finally can lead to cell apoptosis. Neurons have developed their own endogenous cellular protective systems. Some of them are preventing cell death and others are allowing functional recovery after injury. The high efficiency of these mechanisms is crucial for cell survival. In this review we focus on the contribution of the most recently studied endogenous neuroprotective factors involved in retinal ganglion cell (RGC) survival, among which, neurotrophic factors and their signaling pathways, processes regulating the redox status, and different pathways regulating cell death are the most important. Additionally, we summarize currently ongoing clinical trials for therapies for RGC degeneration and optic neuropathies, including glaucoma. Knowledge of the endogenous cellular protective mechanisms may help in the development of effective therapies and potential novel therapeutic targets in order to achieve progress in the treatment of retinal and optic nerve diseases.
关键词： endogenous neuroprotection,optic neuropathy,retinal ganglion cells,cell survival,stress-response
更新于2025-09-04 15:30:14
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Evaluation of the Structure–Function Relationship in Glaucoma Using a Novel Method for Estimating the Number of Retinal Ganglion Cells in the Human Retina
摘要： PURPOSE. We developed a simple method for estimating the number of retinal ganglion cells (RGCs) in the human retina using optical coherence tomography (OCT), compared it to a previous approach, and demonstrated its potential for furthering our understanding of the structure–function relationship in glaucoma. METHODS. Swept-source (ss) OCT data and 10-2 visual ?elds (VFs) were obtained from 43 eyes of 36 healthy controls, and 50 eyes of 50 glaucoma patients and suspects. Using estimates of RGC density from the literature and relatively few assumptions, estimates of the number of RGCs in the macula were obtained based on ssOCT-derived RGC layer thickness measurements. RESULTS. The RGC estimates were in general agreement with previously published values derived from histology, whereas a prior method based on VF sensitivity did not agree as well with histological data and had signi?cantly higher (P ? 0.001) and more variable (P < 0.001) RGC estimates than the new method based on ssOCT. However, the RGC estimates of the new approach were not zero for extreme VF losses, suggesting that a residual, non-RGC contribution needs to be added. Finally, the new ssOCT-derived RGC estimates were signi?cantly (P < 0.001 to P ? 0.018) related to VF sensitivity (Spearman’s q ? 0.26–0.47), and, in contrast to claims made in prior studies, statistically signi?cant RGC loss did not occur more often than statistically signi?cant visual loss. CONCLUSIONS. The novel method for estimating RGCs yields values that are closer to histological estimates than prior methods, while relying on considerably fewer assumptions. Although the value added for clinical applications is yet to be determined, this approach is useful for assessing the structure–function relationship in glaucoma.
关键词： visual ?elds,glaucoma,retinal ganglion cells,structure versus function,macula,optical coherence tomography
更新于2025-09-04 15:30:14
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Retina-V1 model of detectability across the visual field
摘要： A practical model is proposed for predicting the detectability of targets at arbitrary locations in the visual field, in arbitrary gray scale backgrounds, and under photopic viewing conditions. The major factors incorporated into the model include (a) the optical point spread function of the eye, (b) local luminance gain control (Weber’s law), (c) the sampling array of retinal ganglion cells, (d) orientation and spatial frequency–dependent contrast masking, (e) broadband contrast masking, and (f) efficient response pooling. The model is tested against previously reported threshold measurements on uniform backgrounds (the ModelFest data set and data from Foley, Varadharajan, Koh, & Farias, 2007) and against new measurements reported here for several ModelFest targets presented on uniform, 1/f noise, and natural backgrounds at retinal eccentricities ranging from 08 to 108. Although the model has few free parameters, it is able to account quite well for all the threshold measurements.
关键词： spatial vision,natural images,peripheral vision,masking,detection,ganglion cells
更新于2025-09-04 15:30:14
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[IEEE 2018 40th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) - Honolulu, HI (2018.7.18-2018.7.21)] 2018 40th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) - Optic nerve and retinal electrostimulation in rats: direct activation of the retinal ganglion cells
摘要： Visual prosthesis is competing with biological approaches to restore vision to the blind. Understanding and developing the ability to replicate the neural code of the retina are key factors that can bring bionic vision significant advantage. Here, electrically evoked potentials were recorded in anesthetized rats from the dorsal surface of the superior colliculus. Electrical stimuli of different amplitudes were delivered at the retina and the optic nerve. An evoked potential appeared in both cases within the first 5 ms post-stimulus suggesting that this component of the response was initiated by direct activation of the retinal ganglion cells. However, in the case of retinal neurostimulation, a second evoked potential occurred 9.0 ± 3.4 ms after the stimulus delivery. Because this component was not present in the case of optic nerve electrostimulation, it is expected to be originated by the activation of other cells in the retinal network.
关键词： superior colliculus,visual prosthesis,electrostimulation,retinal ganglion cells,optic nerve
更新于2025-09-04 15:30:14
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Protective effects of ciliary neurotrophic factor on the retinal ganglion cells by injure of hydrogen peroxide
摘要： ● AIM: To explore the effect of ciliary neurotrophic factor (CNTF) on retinal ganglion cell (RGC)-5 induced by hydrogen peroxide (H2O2). ● METHODS: After cell adherence, RGC-5 culture medium was changed to contain different concentrations of H2O2 from 50 to 150 μmol/L at four time points (0.5, 1, 1.5 and 2h) to select the concentration and time point for H2O2 induced model. Two different ways of interventions for injured RGC-5 cells respectively were CNTF as an addition in the culture medium or recombinant lentiviral plasmid carrying CNTF gene transfecting bone mesenchymal stem cells (BMSCs) for co-culture with RGC-5. ● RESULTS: Compared to the control group, H2O2 led to RGC-5 death closely associated with concentrations and action time of H2O2 and we chose 125 μmol/L and 2h to establish the H2O2-induced model. While CNTF inhibited the loss of RGC-5 cells obviously with a dose-dependent survival rate. Nevertheless two administration routes had different survival rate yet higher rate in recombinant lentiviral plasmid group but there were no statistically significant differences. ● CONCLUSION: Both the two administration routes of CNTF have effects on RGC-5 cells induced by H2O2. If their own advantages were combined, there may be a better administration route.
关键词： retinal ganglion cells,ciliary neurotrophic factor,neuroprotection,hydrogen peroxide,recombinant lentiviral vector
更新于2025-09-04 15:30:14