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21 pages, 5290 KiB

Open AccessArticle

Temporal Transcriptomic Profiling of the Developing Xenopus laevis Eye

by Samantha J. Hack, Juli Petereit and Kelly Ai-Sun Tseng

Cells 2024, 13(16), 1390; https://doi.org/10.3390/cells13161390 - 21 Aug 2024

Viewed by 491

Abstract

Retinal progenitor cells (RPCs) are a multipotent and highly proliferative population that give rise to all retinal cell types during organogenesis. Defining their molecular signature is a key step towards identifying suitable approaches to treat visual impairments. Here, we performed RNA sequencing of [...] Read more.

Retinal progenitor cells (RPCs) are a multipotent and highly proliferative population that give rise to all retinal cell types during organogenesis. Defining their molecular signature is a key step towards identifying suitable approaches to treat visual impairments. Here, we performed RNA sequencing of whole eyes from Xenopus at three embryonic stages and used differential expression analysis to define the transcriptomic profiles of optic tissues containing proliferating and differentiating RPCs during retinogenesis. Gene Ontology and KEGG pathway analyses showed that genes associated with developmental pathways (including Wnt and Hedgehog signaling) were upregulated during the period of active RPC proliferation in early retinal development (Nieuwkoop Faber st. 24 and 27). Developing eyes had dynamic expression profiles and shifted to enrichment for metabolic processes and phototransduction during RPC progeny specification and differentiation (st. 35). Furthermore, conserved adult eye regeneration genes were also expressed during early retinal development, including sox2, pax6, nrl, and Notch signaling components. The eye transcriptomic profiles presented here span RPC proliferation to retinogenesis and include regrowth-competent stages. Thus, our dataset provides a rich resource to uncover molecular regulators of RPC activity and will allow future studies to address regulators of RPC proliferation during eye repair and regrowth. Full article

(This article belongs to the Special Issue Mechanism of Cell Signaling during Eye Development and Diseases)

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15 pages, 12230 KiB

Open AccessArticle

Chemical (Alkali) Burn-Induced Neurotrophic Keratitis Model in New Zealand Rabbit Investigated Using Medical Clinical Readouts and In Vivo Confocal Microscopy (IVCM)

by Mehak Vohra, Abha Gour, Jyoti Rajput, Bharti Sangwan, Monika Chauhan, Kartik Goel, Ajith Kamath, Umang Mathur, Arun Chandru, Virender Singh Sangwan, Tuhin Bhowmick and Anil Tiwari

Cells 2024, 13(5), 379; https://doi.org/10.3390/cells13050379 - 22 Feb 2024

Cited by 2 | Viewed by 1691

Abstract

Purpose: Chemical eye injury is an acute emergency that can result in vision loss. Neurotrophic keratitis (NK) is the most common long-term manifestation of chemical injury. NK due to alkali burn affects ocular surface health and is one of its most common causes. [...] Read more.

Purpose: Chemical eye injury is an acute emergency that can result in vision loss. Neurotrophic keratitis (NK) is the most common long-term manifestation of chemical injury. NK due to alkali burn affects ocular surface health and is one of its most common causes. Here, we established a rabbit model of corneal alkali burns to evaluate the severity of NK-associated changes. Material methods: Alkali burns were induced in NZ rabbits by treating the cornea with (i) a 5 mm circular filter paper soaked in 0.75 N NaOH for 10 s (Mild NK) and (ii) trephination using a guarded trephine (5 mm diameter and 150-micron depth), followed by alkali burn, with a 5 mm circular filter paper soaked in 0.75 N NaOH for 10 s (a severe form of NK). Immediately after, the cornea was rinsed with 10 mL of normal saline to remove traces of NaOH. Clinical features were evaluated on Day 0, Day 1, Day 7, Day 15, and Day 21 post-alkali burn using a slit lamp, Pentacam, and anterior segment optical coherence tomography (AS-OCT). NK-like changes in epithelium, sub-basal nerve plexus, and stroma were observed using in vivo confocal microscopy (IVCM), and corneal sensation were measured using an aesthesiometer post alkali injury. After 21 days, pro-inflammatory cytokines were evaluated for inflammation through ELISA. Results: Trephination followed by alkali burn resulted in the loss of epithelial layers (manifested using fluorescein stain), extensive edema, and increased corneal thickness (550 µm compared to 380 µm thickness of control) evaluated through AS-OCT and increased opacity score in alkali-treated rabbit (80 compared to 16 controls). IVCM images showed complete loss of nerve fibers, which failed to regenerate over 30 days, and loss of corneal sensation—conditions associated with NK. Cytokines evaluation of IL6, VEGF, and MMP9 indicated an increased angiogenic and pro-inflammatory milieu compared to the milder form of NK and the control. Discussion: Using clinical parameters, we demonstrated that the alkali-treated rabbit model depicts features of NK. Using IVCM in the NaOH burn animal model, we demonstrated a complete loss of nerve fibers with poor self-healing capability associated with sub-basal nerve degeneration and compromised corneal sensation. This pre-clinical rabbit model has implications for future pre-clinical research in neurotrophic keratitis. Full article

(This article belongs to the Special Issue Mechanism of Cell Signaling during Eye Development and Diseases)

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23 pages, 14033 KiB

Open AccessArticle

Conditional Ablation of Spred1 and Spred2 in the Eye Lens Negatively Impacts Its Development and Growth

by Fatima Wazin and Frank J. Lovicu

Cells 2024, 13(4), 290; https://doi.org/10.3390/cells13040290 - 6 Feb 2024

Viewed by 965

Abstract

The development and growth of the eye depends on normal lens morphogenesis and its growth. This growth, in turn, is dependent on coordinated proliferation of the lens epithelial cells and their subsequent differentiation into fiber cells. These cellular processes are tightly regulated to [...] Read more.

The development and growth of the eye depends on normal lens morphogenesis and its growth. This growth, in turn, is dependent on coordinated proliferation of the lens epithelial cells and their subsequent differentiation into fiber cells. These cellular processes are tightly regulated to maintain the precise cellular structure and size of the lens, critical for its transparency and refractive properties. Growth factor-mediated MAPK signaling driven by ERK1/2 has been reported as essential for regulating cellular processes of the lens, with ERK1/2 signaling tightly regulated by endogenous antagonists, including members of the Sprouty and related Spred families. Our previous studies have demonstrated the importance of both these inhibitory molecules in lens and eye development. In this study, we build on these findings to highlight the importance of Spreds in regulating early lens morphogenesis by modulating ERK1/2-mediated lens epithelial cell proliferation and fiber differentiation. Conditional loss of both Spred1 and Spred2 in early lens morphogenesis results in elevated ERK1/2 phosphorylation, hyperproliferation of lens epithelia, and an associated increase in the rate of fiber differentiation. This results in transient microphakia and microphthalmia, which disappears, owing potentially to compensatory Sprouty expression. Our data support an important temporal role for Spreds in the early stages of lens morphogenesis and highlight how negative regulation of ERK1/2 signaling is critical for maintaining lens proliferation and fiber differentiation in situ throughout life. Full article

(This article belongs to the Special Issue Mechanism of Cell Signaling during Eye Development and Diseases)

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13 pages, 3144 KiB

Open AccessArticle

Altered Visual Function in Short-Wave-Sensitive 1 (sws1) Gene Knockout Japanese Medaka (Oryzias latipes) Larvae

by Ke Lu, Jiaqi Wu, Shulin Tang, Yuye Wang, Lixin Zhang, Farui Chai and Xu-Fang Liang

Cells 2023, 12(17), 2157; https://doi.org/10.3390/cells12172157 - 28 Aug 2023

Cited by 1 | Viewed by 1451

Abstract

Visual perception plays a crucial role in foraging, avoiding predators, mate selection, and communication. The regulation of color vision is largely dependent on opsin, which is the first step in the formation of the visual transduction cascade in photoreceptor cells. Short-wave-sensitive 1 ( [...] Read more.

Visual perception plays a crucial role in foraging, avoiding predators, mate selection, and communication. The regulation of color vision is largely dependent on opsin, which is the first step in the formation of the visual transduction cascade in photoreceptor cells. Short-wave-sensitive 1 (sws1) is a visual pigment that mediates short-wavelength light transduction in vertebrates. The depletion of sws1 resulted in increased M-opsin in mice. However, there is still no report on the visual function of sws1 in teleost fish. Here, we constructed the sws1 knockout medaka using CRISPR/Cas9 technology. The 6 dph (days post-hatching) medaka sws1^−/− larvae exhibited significantly decreased food intake and total length at the first feeding stage, and the mRNA levels of orexigenic genes (npy and agrp) were significantly upregulated after feeding. The swimming speed was significantly reduced during the period of dark-light transition stimulation in the sws1-mutant larvae. Histological analysis showed that the thickness of the lens was reduced, whereas the thickness of the ganglion cell layer (GCL) was significantly increased in sws1^−/− medaka larvae. Additionally, the deletion of sws1 decreased the mRNA levels of genes involved in phototransduction (gnb3b, grk7a, grk7b, and pde6c). We also observed increased retinal cell apoptosis and oxidative stress in sws1 knockout medaka larvae. Collectively, these results suggest that sws1 deficiency in medaka larvae may impair visual function and cause retinal cell apoptosis, which is associated with the downregulation of photoconduction expression and oxidative stress. Full article

(This article belongs to the Special Issue Mechanism of Cell Signaling during Eye Development and Diseases)

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Review

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14 pages, 770 KiB

Open AccessReview

A Review of Pathophysiology and Therapeutic Strategies Targeting TGF-β in Graves’ Ophthalmopathy

by Hsin-Ho Chang, Shi-Bei Wu and Chieh-Chih Tsai

Cells 2024, 13(17), 1493; https://doi.org/10.3390/cells13171493 - 5 Sep 2024

Viewed by 596

Abstract

TGF-β plays a pivotal role in the pathogenesis of GO by promoting orbital tissue remodeling and fibrosis. This process involves the stimulation of orbital fibroblasts, leading to myofibroblast differentiation, increased production of inflammatory mediators, and hyaluronan accumulation. Studies have elucidated TGF-β’s role in [...] Read more.

TGF-β plays a pivotal role in the pathogenesis of GO by promoting orbital tissue remodeling and fibrosis. This process involves the stimulation of orbital fibroblasts, leading to myofibroblast differentiation, increased production of inflammatory mediators, and hyaluronan accumulation. Studies have elucidated TGF-β’s role in driving fibrosis and scarring processes through both canonical and non-canonical pathways, particularly resulting in the activation of orbital myofibroblasts and the excessive accumulation of extracellular matrix. Additionally, recent in vitro and in vivo studies have been summarized, highlighting the therapeutic potential of targeting TGF-β signaling pathways, which may offer promising treatment interventions for GO. This review aims to consolidate the current understanding of the multifaceted role of TGF-β in the molecular and cellular pathophysiology in Graves’ ophthalmopathy (GO) by exploring its contributions to fibrosis, inflammation, and immune dysregulation. Additionally, the review investigates the therapeutic potential of inhibiting TGF-β signaling pathways as a strategy for treating GO. Full article

(This article belongs to the Special Issue Mechanism of Cell Signaling during Eye Development and Diseases)

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21 pages, 625 KiB

Open AccessReview

TGF-β-Based Therapies for Treating Ocular Surface Disorders

by Fernando T. Ogata, Sudhir Verma, Vivien J. Coulson-Thomas and Tarsis F. Gesteira

Cells 2024, 13(13), 1105; https://doi.org/10.3390/cells13131105 - 26 Jun 2024

Cited by 1 | Viewed by 1325

Abstract

The cornea is continuously exposed to injuries, ranging from minor scratches to deep traumas. An effective healing mechanism is crucial for the cornea to restore its structure and function following major and minor insults. Transforming Growth Factor-Beta (TGF-β), a versatile signaling molecule that [...] Read more.

The cornea is continuously exposed to injuries, ranging from minor scratches to deep traumas. An effective healing mechanism is crucial for the cornea to restore its structure and function following major and minor insults. Transforming Growth Factor-Beta (TGF-β), a versatile signaling molecule that coordinates various cell responses, has a central role in corneal wound healing. Upon corneal injury, TGF-β is rapidly released into the extracellular environment, triggering cell migration and proliferation, the differentiation of keratocytes into myofibroblasts, and the initiation of the repair process. TGF-β-mediated processes are essential for wound closure; however, excessive levels of TGF-β can lead to fibrosis and scarring, causing impaired vision. Three primary isoforms of TGF-β exist—TGF-β1, TGF-β2, and TGF-β3. Although TGF-β isoforms share many structural and functional similarities, they present distinct roles in corneal regeneration, which adds an additional layer of complexity to understand the role of TGF-β in corneal wound healing. Further, aberrant TGF-β activity has been linked to various corneal pathologies, such as scarring and Peter’s Anomaly. Thus, understanding the molecular and cellular mechanisms by which TGF-β1-3 regulate corneal wound healing will enable the development of potential therapeutic interventions targeting the key molecule in this process. Herein, we summarize the multifaceted roles of TGF-β in corneal wound healing, dissecting its mechanisms of action and interactions with other molecules, and outline its role in corneal pathogenesis. Full article

(This article belongs to the Special Issue Mechanism of Cell Signaling during Eye Development and Diseases)

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16 pages, 1504 KiB

Open AccessReview

The Molecular Mechanisms Responsible for Tear Hyperosmolarity-Induced Pathological Changes in the Eyes of Dry Eye Disease Patients

by Carl Randall Harrell, Lisa Feulner, Valentin Djonov, Dragica Pavlovic and Vladislav Volarevic

Cells 2023, 12(23), 2755; https://doi.org/10.3390/cells12232755 - 1 Dec 2023

Cited by 2 | Viewed by 4104

Abstract

Dry eye disease (DED) is a multifactorial disorder of the lacrimal system and ocular surface, characterized by a deficiency in the quality and/or quantity of the tear fluid. The multifactorial nature of DED encompasses a number of interconnected underlying pathologies, including loss of [...] Read more.

Dry eye disease (DED) is a multifactorial disorder of the lacrimal system and ocular surface, characterized by a deficiency in the quality and/or quantity of the tear fluid. The multifactorial nature of DED encompasses a number of interconnected underlying pathologies, including loss of homeostasis, instability and hyperosmolarity of the tears, and the induction and propagation of detrimental inflammatory responses in the eyes, which finally results in the development of neurosensory dysfunction and visual disruption. Dryness, grittiness, scratchiness, discomfort, inflammation, burning, watering, ocular fatigue, pain, and decreased functional visual acuity are common symptoms of DED. Eye dysfunction drastically attenuates patients’ quality of life. Accordingly, a better understanding of the pathogenic processes that regulate the development and progression of DED is crucially important for the establishment of new and more effective DED-related treatment approaches, which would significantly improve the quality of life of DED patients. Since the process of osmoregulation, which guards the ocular surface epithelia and maintains normal vision, is affected when the osmolarity of the tears is greater than that of the epithelial cells, tear hyperosmolarity (THO) is considered an initial, important step in the development, progression, and aggravation of DED. In order to delineate the role of THO in the pathogenesis of DED, in this review article, we summarize current knowledge related to the molecular mechanisms responsible for the development of THO-induced pathological changes in the eyes of DED patients, and we briefly discuss the therapeutic potential of hypo-osmotic eye drops in DED treatment. Full article

(This article belongs to the Special Issue Mechanism of Cell Signaling during Eye Development and Diseases)

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20 pages, 2385 KiB

Open AccessReview

Limbal Epithelial Stem Cells in the Diabetic Cornea

by Lamia Nureen and Nick Di Girolamo

Cells 2023, 12(20), 2458; https://doi.org/10.3390/cells12202458 - 16 Oct 2023

Cited by 3 | Viewed by 2035

Abstract

Continuous replenishment of the corneal epithelium is pivotal for maintaining optical transparency and achieving optimal visual perception. This dynamic process is driven by limbal epithelial stem cells (LESCs) located at the junction between the cornea and conjunctiva, which is otherwise known as the [...] Read more.

Continuous replenishment of the corneal epithelium is pivotal for maintaining optical transparency and achieving optimal visual perception. This dynamic process is driven by limbal epithelial stem cells (LESCs) located at the junction between the cornea and conjunctiva, which is otherwise known as the limbus. In patients afflicted with diabetes, hyperglycemia-induced impairments in corneal epithelial regeneration results in persistent epithelial and other defects on the ocular surface, termed diabetic keratopathy (DK), which progressively diminish vision and quality of life. Reports of delayed corneal wound healing and the reduced expression of putative stem cell markers in diabetic relative to healthy eyes suggest that the pathogenesis of DK may be associated with the abnormal activity of LESCs. However, the precise role of these cells in diabetic corneal disease is poorly understood and yet to be comprehensively explored. Herein, we review existing literature highlighting aberrant LESC activity in diabetes, focusing on factors that influence their form and function, and emerging therapies to correct these defects. The consequences of malfunctioning or depleted LESC stocks in DK and limbal stem cell deficiency (LSCD) are also discussed. These insights could be exploited to identify novel targets for improving the management of ocular surface complications that manifest in patients with diabetes. Full article

(This article belongs to the Special Issue Mechanism of Cell Signaling during Eye Development and Diseases)

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