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Keywords = corneal endothelial regeneration

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20 pages, 704 KiB  
Review
Clinical Applications of Corneal Cells Derived from Induced Pluripotent Stem Cells
by Yixin Luan, Aytan Musayeva, Jina Kim, Debbie Le Blon, Bert van den Bogerd, Mor M. Dickman, Vanessa L. S. LaPointe, Sorcha Ni Dhubhghaill and Silke Oellerich
Biomolecules 2025, 15(8), 1139; https://doi.org/10.3390/biom15081139 - 7 Aug 2025
Abstract
Corneal diseases are among the leading causes of blindness worldwide and the standard treatment is the transplantation of corneal donor tissue. Treatment for cornea-related visual impairment and blindness is, however, often constrained by the global shortage of suitable donor grafts. To alleviate the [...] Read more.
Corneal diseases are among the leading causes of blindness worldwide and the standard treatment is the transplantation of corneal donor tissue. Treatment for cornea-related visual impairment and blindness is, however, often constrained by the global shortage of suitable donor grafts. To alleviate the shortage of corneal donor tissue, new treatment options have been explored in the last decade. The discovery of induced pluripotent stem cells (iPSCs), which has revolutionized regenerative medicine, offers immense potential for corneal repair and regeneration. Using iPSCs can provide a renewable source for generating various corneal cell types, including corneal epithelial cells, stromal keratocytes, and corneal endothelial cells. To document the recent progress towards the clinical application of iPSC-derived corneal cells, this review summarizes the latest advancements in iPSC-derived corneal cell therapies, ranging from differentiation protocols and preclinical studies to the first clinical trials, and discusses the challenges for successful translation to the clinic. Full article
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29 pages, 2822 KiB  
Article
Impact of Well-Controlled Type 2 Diabetes on Corneal Endothelium Following Cataract Surgery: A Prospective Longitudinal Analysis
by Aleksandra Opala, Łukasz Kołodziejski and Iwona Grabska-Liberek
J. Clin. Med. 2025, 14(10), 3603; https://doi.org/10.3390/jcm14103603 - 21 May 2025
Viewed by 585
Abstract
Background: The aim of this study was to evaluate corneal endothelial changes following phacoemulsification cataract surgery with intraocular lens implantation in patients with type 2 diabetes (study group) and without diabetes (control group). The study aimed to determine the extent of endothelial cell [...] Read more.
Background: The aim of this study was to evaluate corneal endothelial changes following phacoemulsification cataract surgery with intraocular lens implantation in patients with type 2 diabetes (study group) and without diabetes (control group). The study aimed to determine the extent of endothelial cell damage and the regenerative capacity of the cornea in patients with well-controlled diabetes. Methods: This study compared corneal endothelial parameters in 80 eyes (80 patients) with well-controlled type 2 diabetes and 80 eyes (80 patients) without diabetes, all of whom underwent uneventful phacoemulsification cataract surgery. Patients were examined preoperatively and at 14 days, 3 months, and 6–8 months postoperatively. Endothelial cell density (ECD), percentage of hexagonal cells (%HEX), cell size variability (CV), and central corneal thickness (CCT) were assessed using a specular microscope. Visual acuity, intraocular pressure (IOP), and cumulative dissipated energy (CDE) during phacoemulsification were also measured. Results: The study and control groups were matched for age and sex. Preoperatively, patients with type 2 diabetes had significantly lower endothelial cell density (2480.76 ± 303.48 cells/mm2) compared to the control group (2629.64 ± 304.73 cells/mm2, p = 0.002). Visual acuity was also significantly lower in the study group (0.44 ± 0.18) than in the control group (0.50 ± 0.19, p = 0.049). No significant preoperative differences were observed in IOP, CV, %HEX, or CCT. Postoperatively, both groups experienced ECD decline: −18.44%, −18.77%, and −19.05% in the study group and −15.12%, −16.42%, and −16.73% in the control group at 14 days, 3 months, and 6–8 months, respectively. Differences between groups were not statistically significant (p = 0.285). A significant %HEX decrease was observed in both groups at all time points, with a greater decline in the study group at 14 days and 3 months. CV significantly increased in both groups at 14 days and 3 months postoperatively, but no significant difference was found between groups. A significant increase in CCT was observed at 14 days and 3 months postoperatively, with a greater increase in the study group at 14 days. Preoperative visual acuity negatively correlated with CDE in both groups. Additionally, CDE negatively correlated with ECD at all time points. Conclusions: Endothelial cell density is lower in patients with well-controlled type 2 diabetes than in non-diabetic individuals. Both groups are at risk of endothelial cell loss during phacoemulsification. Despite good glycemic control and comparable preoperative endothelial morphology, the cornea in diabetic patients is more vulnerable to damage, with a prolonged regeneration process. The impaired regenerative capacity of the corneal endothelium suggests the need for additional precautions during cataract surgery in diabetic patients. Despite ECD decline and delayed endothelial regeneration, the functional status of the cornea, as indicated by visual acuity and CCT, remains stable. The adequate corneal endothelial cell reserve in well-controlled type 2 diabetes patients allows for cataract surgery without significant corneal complications. Full article
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9 pages, 731 KiB  
Review
Rho-Kinase Inhibitors in the Management of Fuchs Endothelial Corneal Dystrophy: A Review
by Anđela Jukić, Ana Pupić Bakrač, Biljana Đapic Ivančić, Andrijana Kopić, Ana Meter, Rajka Kasalica Žužul, Josip Pavan and Tomislav Jukić
Medicina 2025, 61(5), 772; https://doi.org/10.3390/medicina61050772 - 22 Apr 2025
Viewed by 1414
Abstract
Fuchs endothelial corneal dystrophy (FECD) is the most common corneal endothelial dystrophy. It is characterized by the progressive loss of corneal endothelial cells (CECs), guttae formation on the Descemet membrane, and corneal edema, leading to visual impairment. Corneal transplantation remains the standard treatment, [...] Read more.
Fuchs endothelial corneal dystrophy (FECD) is the most common corneal endothelial dystrophy. It is characterized by the progressive loss of corneal endothelial cells (CECs), guttae formation on the Descemet membrane, and corneal edema, leading to visual impairment. Corneal transplantation remains the standard treatment, but it has limitations such as donor shortages, infection risk, and graft rejection. Rho-kinase (ROCK) inhibitors have emerged as a promising pharmacological alternative. These agents promote CEC proliferation, migration, and adhesion while inhibiting apoptosis and enhancing corneal endothelial wound healing. Several studies have demonstrated the efficacy of ROCK inhibitors in improving corneal clarity and endothelial function, particularly when used as an adjunct to Descemet Stripping Only (DSO) surgery. Additionally, they show potential in preventing corneal edema in FECD patients undergoing cataract surgery. The methodology involved a literature search through the PubMed and Medline databases using relevant keywords. Only peer-reviewed articles in English were included, with additional references from selected articles reviewed to ensure comprehensive coverage. ROCK inhibitors offer a novel pharmacological approach to managing FECD. They have shown potential in promoting endothelial cell regeneration and improving corneal functIion. Despite promising results, further research is required to determine ROCK inhibitors’ long-term safety, optimal dosing, and efficacy in surgical and non-surgical FECD patients. Their potential to delay or prevent corneal transplantation represents a significant advancement in FECD management. Full article
(This article belongs to the Special Issue Advances in Corneal Management)
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43 pages, 4206 KiB  
Review
Advancements in Polymer Biomaterials as Scaffolds for Corneal Endothelium Tissue Engineering
by Kevin Y. Wu, Myriam Belaiche, Ying Wen, Mazen Y. Choulakian and Simon D. Tran
Polymers 2024, 16(20), 2882; https://doi.org/10.3390/polym16202882 - 12 Oct 2024
Cited by 4 | Viewed by 3237
Abstract
Corneal endothelial dysfunction is a leading cause of vision loss globally, frequently requiring corneal transplantation. However, the limited availability of donor tissues, particularly in developing countries, has spurred on the exploration of tissue engineering strategies, with a focus on polymer biomaterials as scaffolds [...] Read more.
Corneal endothelial dysfunction is a leading cause of vision loss globally, frequently requiring corneal transplantation. However, the limited availability of donor tissues, particularly in developing countries, has spurred on the exploration of tissue engineering strategies, with a focus on polymer biomaterials as scaffolds for corneal endotlhelium regeneration. This review provides a comprehensive overview of the advancements in polymer biomaterials, focusing on their role in supporting the growth, differentiation, and functional maintenance of human corneal endothelial cells (CECs). Key properties of scaffold materials, including optical clarity, biocompatibility, biodegradability, mechanical stability, permeability, and surface wettability, are discussed in detail. The review also explores the latest innovations in micro- and nano-topological morphologies, fabrication techniques such as electrospinning and 3D/4D bioprinting, and the integration of drug delivery systems into scaffolds. Despite significant progress, challenges remain in translating these technologies to clinical applications. Future directions for research are highlighted, including the need for improved biomaterial combinations, a deeper understanding of CEC biology, and the development of scalable manufacturing processes. This review aims to serve as a resource for researchers and clinician–scientists seeking to advance the field of corneal endothelium tissue engineering. Full article
(This article belongs to the Section Biobased and Biodegradable Polymers)
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14 pages, 4738 KiB  
Article
Hepatocyte Growth Factor Modulates Corneal Endothelial Wound Healing In Vitro
by Merle Tratnig-Frankl, Nikolaus Luft, Guiseppe Magistro, Siegfried Priglinger, Andreas Ohlmann and Stefan Kassumeh
Int. J. Mol. Sci. 2024, 25(17), 9382; https://doi.org/10.3390/ijms25179382 - 29 Aug 2024
Viewed by 1479
Abstract
In this study, we assessed the impact of hepatocyte growth factor (HGF) on corneal endothelial cells (CECs), finding that HGF concentrations of 100–250 ng/mL significantly increased CEC proliferation by 30%, migration by 32% and improved survival under oxidative stress by 28% compared to [...] Read more.
In this study, we assessed the impact of hepatocyte growth factor (HGF) on corneal endothelial cells (CECs), finding that HGF concentrations of 100–250 ng/mL significantly increased CEC proliferation by 30%, migration by 32% and improved survival under oxidative stress by 28% compared to untreated controls (p < 0.05). The primary objective was to identify non-fibrotic pharmacological strategies to enhance corneal endothelial regeneration, addressing a critical need in conditions like Fuchs’ endothelial dystrophy (FED), where donor tissue is scarce. To confirm the endothelial nature of the cultured CECs, Na+/K+-ATPase immunohistochemistry was performed. Proliferation rates were determined through BrdU incorporation assays, while cell migration was assessed via scratch assays. Cell viability was evaluated under normal and oxidative stress conditions using WST-1 assays. To ensure that HGF treatment did not trigger epithelial-mesenchymal transition, which could lead to undesirable fibrotic changes, α-SMA staining was conducted. These comprehensive methodologies provided robust data on the effects of HGF, confirming its potential as a therapeutic agent for corneal endothelial repair without inducing harmful EMT, as indicated by the absence of α-SMA expression. These findings suggest that HGF holds therapeutic promise for enhancing corneal endothelial repair, warranting further investigation in in vivo models to confirm its clinical applicability. Full article
(This article belongs to the Special Issue Functional Roles of Epithelial and Endothelial Cells)
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16 pages, 2562 KiB  
Article
Immunophenotypical Characterization of Limbal Mesenchymal Stromal Cell Subsets during In Vitro Expansion
by Sara Aghazadeh, Qiuyue Peng, Fereshteh Dardmeh, Jesper Østergaard Hjortdal, Vladimir Zachar and Hiva Alipour
Int. J. Mol. Sci. 2024, 25(16), 8684; https://doi.org/10.3390/ijms25168684 - 9 Aug 2024
Cited by 1 | Viewed by 1474
Abstract
Limbal mesenchymal stromal cells (LMSCs) reside in the limbal niche, supporting corneal integrity and facilitating regeneration. While mesenchymal stem/stromal cells (MSCs) are used in regenerative therapies, there is limited knowledge about LMSC subpopulations and their characteristics. This study characterized human LMSC subpopulations through [...] Read more.
Limbal mesenchymal stromal cells (LMSCs) reside in the limbal niche, supporting corneal integrity and facilitating regeneration. While mesenchymal stem/stromal cells (MSCs) are used in regenerative therapies, there is limited knowledge about LMSC subpopulations and their characteristics. This study characterized human LMSC subpopulations through the flow cytometric assessment of fifteen cell surface markers, including MSC, wound healing, immune regulation, ASC, endothelial, and differentiation markers. Primary LMSCs were established from remnant human corneal transplant specimens and passaged eight times to observe changes during subculture. The results showed the consistent expression of typical MSC markers and distinct subpopulations with the passage-dependent expression of wound healing, immune regulation, and differentiation markers. High CD166 and CD248 expressions indicated a crucial role in ocular surface repair. CD29 expression suggested an immunoregulatory role. Comparable pigment-epithelial-derived factor (PEDF) expression supported anti-inflammatory and anti-angiogenic roles. Sustained CD201 expression indicated maintained differentiation capability, while VEGFR2 expression suggested potential endothelial differentiation. LMSCs showed higher VEGF expression than fibroblasts and endothelial cells, suggesting a potential contribution to ocular surface regeneration through the modulation of angiogenesis and inflammation. These findings highlight the heterogeneity and multipotent potential of LMSC subpopulations during in vitro expansion, informing the development of standardized protocols for regenerative therapies and improving treatments for ocular surface disorders. Full article
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31 pages, 2714 KiB  
Review
Mesenchymal Stem Cells and Exosomes: A Novel Therapeutic Approach for Corneal Diseases
by Basanta Bhujel, Se-Heon Oh, Chang-Min Kim, Ye-Ji Yoon, Young-Jae Kim, Ho-Seok Chung, Eun-Ah Ye, Hun Lee and Jae-Yong Kim
Int. J. Mol. Sci. 2023, 24(13), 10917; https://doi.org/10.3390/ijms241310917 - 30 Jun 2023
Cited by 33 | Viewed by 5273
Abstract
The cornea, with its delicate structure, is vulnerable to damage from physical, chemical, and genetic factors. Corneal transplantation, including penetrating and lamellar keratoplasties, can restore the functions of the cornea in cases of severe damage. However, the process of corneal transplantation presents considerable [...] Read more.
The cornea, with its delicate structure, is vulnerable to damage from physical, chemical, and genetic factors. Corneal transplantation, including penetrating and lamellar keratoplasties, can restore the functions of the cornea in cases of severe damage. However, the process of corneal transplantation presents considerable obstacles, including a shortage of available donors, the risk of severe graft rejection, and potentially life-threatening complications. Over the past few decades, mesenchymal stem cell (MSC) therapy has become a novel alternative approach to corneal regeneration. Numerous studies have demonstrated the potential of MSCs to differentiate into different corneal cell types, such as keratocytes, epithelial cells, and endothelial cells. MSCs are considered a suitable candidate for corneal regeneration because of their promising therapeutic perspective and beneficial properties. MSCs compromise unique immunomodulation, anti-angiogenesis, and anti-inflammatory properties and secrete various growth factors, thus promoting corneal reconstruction. These effects in corneal engineering are mediated by MSCs differentiating into different lineages and paracrine action via exosomes. Early studies have proven the roles of MSC-derived exosomes in corneal regeneration by reducing inflammation, inhibiting neovascularization, and angiogenesis, and by promoting cell proliferation. This review highlights the contribution of MSCs and MSC-derived exosomes, their current usage status to overcome corneal disease, and their potential to restore different corneal layers as novel therapeutic agents. It also discusses feasible future possibilities, applications, challenges, and opportunities for future research in this field. Full article
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20 pages, 12725 KiB  
Article
A p-Tyr42 RhoA Inhibitor Promotes the Regeneration of Human Corneal Endothelial Cells by Ameliorating Cellular Senescence
by Hyeon Jung Kim, Jin Sun Hwang, Kyung Bo Noh, Sun-Hee Oh, Jae-Bong Park and Young Joo Shin
Antioxidants 2023, 12(6), 1186; https://doi.org/10.3390/antiox12061186 - 30 May 2023
Viewed by 1942
Abstract
The development of treatment strategies for human corneal endothelial cells (hCECs) disease is necessary because hCECs do not regenerate in vivo due to the properties that are similar to senescence. This study is performed to investigate the role of a p-Tyr42 RhoA inhibitor [...] Read more.
The development of treatment strategies for human corneal endothelial cells (hCECs) disease is necessary because hCECs do not regenerate in vivo due to the properties that are similar to senescence. This study is performed to investigate the role of a p-Tyr42 RhoA inhibitor (MH4, ELMED Inc., Chuncheon) in transforming growth factor-beta (TGF-β)- or H2O2-induced cellular senescence of hCECs. Cultured hCECs were treated with MH4. The cell shape, proliferation rate, and cell cycle phases were analyzed. Moreover, cell adhesion assays and immunofluorescence staining for F-actin, Ki-67, and E-cadherin were performed. Additionally, the cells were treated with TGF-β or H2O2 to induce senescence, and mitochondrial oxidative reactive oxygen species (ROS) levels, mitochondrial membrane potential, and NF-κB translocation were evaluated. LC3II/LC3I levels were determined using Western blotting to analyze autophagy. MH4 promotes hCEC proliferation, shifts the cell cycle, attenuates actin distribution, and increases E-cadherin expression. TGF-β and H2O2 induce senescence by increasing mitochondrial ROS levels and NF-κB translocation into the nucleus; however, this effect is attenuated by MH4. Moreover, TGF-β and H2O2 decrease the mitochondrial membrane potential and induce autophagy, while MH4 reverses these effects. In conclusion, MH4, a p-Tyr42 RhoA inhibitor, promotes the regeneration of hCECs and protects hCECs against TGF-β- and H2O2-induced senescence via the ROS/NF-κB/mitochondrial pathway. Full article
(This article belongs to the Section Health Outcomes of Antioxidants and Oxidative Stress)
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22 pages, 2509 KiB  
Review
Extracellular-Vesicle-Based Therapeutics in Neuro-Ophthalmic Disorders
by Hamed Massoumi, Sohil Amin, Mohammad Soleimani, Bita Momenaei, Mohammad Javad Ashraf, Victor H. Guaiquil, Peiman Hematti, Mark I. Rosenblatt, Ali R. Djalilian and Elmira Jalilian
Int. J. Mol. Sci. 2023, 24(10), 9006; https://doi.org/10.3390/ijms24109006 - 19 May 2023
Cited by 22 | Viewed by 4501
Abstract
Extracellular vesicles (EVs) have been recognized as promising candidates for developing novel therapeutics for a wide range of pathologies, including ocular disorders, due to their ability to deliver a diverse array of bioactive molecules, including proteins, lipids, and nucleic acids, to recipient cells. [...] Read more.
Extracellular vesicles (EVs) have been recognized as promising candidates for developing novel therapeutics for a wide range of pathologies, including ocular disorders, due to their ability to deliver a diverse array of bioactive molecules, including proteins, lipids, and nucleic acids, to recipient cells. Recent studies have shown that EVs derived from various cell types, including mesenchymal stromal cells (MSCs), retinal pigment epithelium cells, and endothelial cells, have therapeutic potential in ocular disorders, such as corneal injury and diabetic retinopathy. EVs exert their effects through various mechanisms, including promoting cell survival, reducing inflammation, and inducing tissue regeneration. Furthermore, EVs have shown promise in promoting nerve regeneration in ocular diseases. In particular, EVs derived from MSCs have been demonstrated to promote axonal regeneration and functional recovery in various animal models of optic nerve injury and glaucoma. EVs contain various neurotrophic factors and cytokines that can enhance neuronal survival and regeneration, promote angiogenesis, and modulate inflammation in the retina and optic nerve. Additionally, in experimental models, the application of EVs as a delivery platform for therapeutic molecules has revealed great promise in the treatment of ocular disorders. However, the clinical translation of EV-based therapies faces several challenges, and further preclinical and clinical studies are needed to fully explore the therapeutic potential of EVs in ocular disorders and to address the challenges for their successful clinical translation. In this review, we will provide an overview of different types of EVs and their cargo, as well as the techniques used for their isolation and characterization. We will then review the preclinical and clinical studies that have explored the role of EVs in the treatment of ocular disorders, highlighting their therapeutic potential and the challenges that need to be addressed for their clinical translation. Finally, we will discuss the future directions of EV-based therapeutics in ocular disorders. Overall, this review aims to provide a comprehensive overview of the current state of the art of EV-based therapeutics in ophthalmic disorders, with a focus on their potential for nerve regeneration in ocular diseases. Full article
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17 pages, 3505 KiB  
Article
MiR-302a Regenerates Human Corneal Endothelial Cells against IFN-γ-Induced Cell Death
by Se-Hie Park, Jin-Sun Hwang, Sun-Hee Oh and Young-Joo Shin
Cells 2023, 12(1), 36; https://doi.org/10.3390/cells12010036 - 22 Dec 2022
Cited by 5 | Viewed by 2292
Abstract
Damage to human corneal endothelial cells (hCECs) leads to bullous keratopathy because these cells cannot be regenerated in vivo. In this study, we investigated the protective role of microRNA (miR)-302a against interferon-γ (IFN-γ)-induced senescence and cell death of hCECs. Cultured hCECs were transfected [...] Read more.
Damage to human corneal endothelial cells (hCECs) leads to bullous keratopathy because these cells cannot be regenerated in vivo. In this study, we investigated the protective role of microRNA (miR)-302a against interferon-γ (IFN-γ)-induced senescence and cell death of hCECs. Cultured hCECs were transfected with miR-302a and treated with IFN-γ (20 ng/mL) to evaluate the protective effect of miR-302a on IFN-γ-induced cell death. Senescence was evaluated by the senescence-associated β-galactosidase (SA-β-gal) assay, and the secretion of senescence-associated secretory phenotype (SASP) factors was analyzed. Mitochondrial function and endoplasmic reticulum (ER) stress were assessed. We revealed that miR-302a enhanced the cell viability and proliferation of hCECs and that IFN-γ increased the cell size, the number of SA-β-gal-positive cells, and SASP factors, and arrested the cell cycle, which was eliminated by miR-302a. miR-302a ameliorated mitochondrial oxidative stress and ER stress levels which were induced by IFN-γ. IFN-γ decreased the mitochondrial membrane potential and promoted autophagy, which was eliminated by miR-302a. The in vivo study showed that regeneration of rat CECs was promoted in the miR-302a group by inhibiting IFN-γ and enhancing mitochondrial function. In conclusion, miR-302a eliminated IFN-γ-induced senescence and cellular damage by regulating the oxidative and ER stress, and promoting the proliferation of CECs. Therefore, miR-302a may be a therapeutic option to protect hCECs against IFN-γ-induced stress. Full article
(This article belongs to the Section Cellular Aging)
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15 pages, 2836 KiB  
Article
Novel ROCK Inhibitors, Sovesudil and PHP-0961, Enhance Proliferation, Adhesion and Migration of Corneal Endothelial Cells
by Kyung Wook Kim, Young Joo Shin and Sammy Chi Sam Lee
Int. J. Mol. Sci. 2022, 23(23), 14690; https://doi.org/10.3390/ijms232314690 - 24 Nov 2022
Cited by 8 | Viewed by 2380
Abstract
The loss or dysfunction of human corneal endothelial cells (hCEnCs) is a leading cause of blindness due to corneal failure. Corneal transplantation with a healthy donor cornea has been the only available treatment for corneal endothelial disease. However, the need for way to [...] Read more.
The loss or dysfunction of human corneal endothelial cells (hCEnCs) is a leading cause of blindness due to corneal failure. Corneal transplantation with a healthy donor cornea has been the only available treatment for corneal endothelial disease. However, the need for way to regenerate the CEnCs has been increased due to the global shortage of donor corneas. The aim of the study is to investigate whether novel Rho-kinase (ROCK) inhibitors can induce the cultivation and regeneration of hCEnCs. Cultured hCEnCs were treated with Y-27632, sovesudil, or PHP-0961 for 24 h. Cellular responses, including cell viability, cytotoxicity, proliferation, and Ki67 expression with ROCK inhibitors were evaluated. We also evaluated wound healing and cell adhesion assays. Porcine corneas were used ex vivo to evaluate the effects of Y-27632, sovesudil, and PHP-0961 on wound healing and regeneration. We performed live/dead cell assays and immunofluorescence staining for SRY (sex determining region Y)-box 2 (SOX2), β-catenin, and ZO-1 on porcine corneas after ROCK inhibitor treatments. Cell viability, cell proliferation rate, and the number of Ki67-positive cells were higher in Y-27632, sovesudil and PHP-0961 treated cells compared to the control. There was no difference in LDH cytotoxicity test between any groups. Cells treated with Y-27632, sovesudil and PHP-0961 showed faster migration, wound healing, and cell adhesion. In the porcine ex vivo experiments, wound healing, the number of live cells, and SOX2-positive cells were higher in Y-27632, sovesudil and PHP-0961 treated corneas. In all experiments, sovesudil and PHP-0961, the novel ROCK inhibitors, were equal or superior to the results of the ROCK inhibitor positive control, Y-27632. In conclusion, sovesudil and PHP-0961, novel ROCK inhibitors have the capacity to regenerate hCEnCs by enhancing cell proliferation and adhesion between cells. Full article
(This article belongs to the Section Molecular Biology)
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19 pages, 8053 KiB  
Article
Expression Pattern of Tenascin-C, Matrilin-2, and Aggrecan in Diseases Affecting the Corneal Endothelium
by Gréta Varkoly, Tibor G. Hortobágyi, Enikő Gebri, János Bencze, Tibor Hortobágyi and László Módis
J. Clin. Med. 2022, 11(20), 5991; https://doi.org/10.3390/jcm11205991 - 11 Oct 2022
Cited by 1 | Viewed by 3115
Abstract
Purpose: The aim of this study was to examine the expression pattern of tenascin-C, matrilin-2, and aggrecan in irreversible corneal endothelial pathology such as pseudophakic bullous keratopathy (PBK) and Fuchs’ endothelial corneal dystrophy (FECD), which most frequently require corneal transplantation. Materials and methods: [...] Read more.
Purpose: The aim of this study was to examine the expression pattern of tenascin-C, matrilin-2, and aggrecan in irreversible corneal endothelial pathology such as pseudophakic bullous keratopathy (PBK) and Fuchs’ endothelial corneal dystrophy (FECD), which most frequently require corneal transplantation. Materials and methods: Histological specimens of corneal buttons removed during keratoplasty were investigated in PBK (n = 20) and FECD (n = 9) and compared to healthy control corneas (n = 10). The sections were studied by chromogenic immunohistochemistry (CHR-IHC) and submitted for evaluation by two investigators. Semiquantitative scoring (0 to 3+) was applied according to standardized methods at high magnification (400x). Each layer of the cornea was investigated; in addition, the stroma was subdivided into anterior, middle, and posterior parts for more precise analysis. In case of non-parametric distribution Mann–Whitney test was applied to compare two groups. Kruskal–Wallis and Dunn’s multiple comparisons tests have been applied for comparison of the chromogenic IHC signal intensity among corneal layers within the control and patient groups. Differences of p < 0.05 were considered as significant. Results: Significantly elevated tenascin-C immunopositivity was present in the epithelium and every layer of the stroma in both pathologic conditions as compared to normal controls. In addition, also significantly stronger matrilin-2 positivity was detected in the epithelium; however, weaker reaction was present in the endothelium in PBK cases. Minimal, but significantly elevated immunopositivity could be observed in the anterior and posterior stroma in the FECD group. Additionally, minimally, but significantly higher aggrecan immunoreaction was present in the anterior stroma in PBK and in the posterior stroma in both endothelial disorders. All three antibodies disclosed the strongest reaction in the posterior stroma either in PBK or in FECD cases. Conclusions: These extracellular matrix molecules disclosed up to moderate immunopositivity in the corneal layers in varying extents. Through their networking, bridging, and adhesive abilities these proteins are involved in corneal regeneration and tissue reorganization in endothelial dysfunction. Full article
(This article belongs to the Section Ophthalmology)
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23 pages, 1566 KiB  
Review
Alginate-Based Composites for Corneal Regeneration: The Optimization of a Biomaterial to Overcome Its Limits
by Martine Tarsitano, Maria Chiara Cristiano, Massimo Fresta, Donatella Paolino and Concetta Rafaniello
Gels 2022, 8(7), 431; https://doi.org/10.3390/gels8070431 - 10 Jul 2022
Cited by 21 | Viewed by 4443
Abstract
For many years, corneal transplantation has been the first-choice treatment for irreversible damage affecting the anterior part of the eye. However, the low number of cornea donors and cases of graft rejection highlighted the need to replace donor corneas with new biomaterials. Tissue [...] Read more.
For many years, corneal transplantation has been the first-choice treatment for irreversible damage affecting the anterior part of the eye. However, the low number of cornea donors and cases of graft rejection highlighted the need to replace donor corneas with new biomaterials. Tissue engineering plays a fundamental role in achieving this goal through challenging research into a construct that must reflect all the properties of the cornea that are essential to ensure correct vision. In this review, the anatomy and physiology of the cornea are described to point out the main roles of the corneal layers to be compensated and all the requirements expected from the material to be manufactured. Then, a deep investigation of alginate as a suitable alternative to donor tissue was conducted. Thanks to its adaptability, transparency and low immunogenicity, alginate has emerged as a promising candidate for the realization of bioengineered materials for corneal regeneration. Chemical modifications and the blending of alginate with other functional compounds allow the control of its mechanical, degradation and cell-proliferation features, enabling it to go beyond its limits, improving its functionality in the field of corneal tissue engineering and regenerative medicine. Full article
(This article belongs to the Collection Hydrogel in Tissue Engineering and Regenerative Medicine)
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18 pages, 5607 KiB  
Article
Phenotypic and Transcriptomics Analyses Reveal Underlying Mechanisms in a Mouse Model of Corneal Bee Sting
by Yanzi Wang, Honghua Kang, Mengyi Jin, Guoliang Wang, Weifang Ma, Zhen Liu, Yuhua Xue and Cheng Li
Toxins 2022, 14(7), 468; https://doi.org/10.3390/toxins14070468 - 8 Jul 2022
Cited by 1 | Viewed by 3788
Abstract
Corneal bee sting (CBS) is one of the most common ocular traumas and can lead to blindness. The ophthalmic manifestations are caused by direct mechanical effects of bee stings, toxic effects, and host immune responses to bee venom (BV); however, the underlying pathogenesis [...] Read more.
Corneal bee sting (CBS) is one of the most common ocular traumas and can lead to blindness. The ophthalmic manifestations are caused by direct mechanical effects of bee stings, toxic effects, and host immune responses to bee venom (BV); however, the underlying pathogenesis remains unclear. Clinically, topical steroids and antibiotics are routinely used to treat CBS patients but the specific drug targets are unknown; therefore, it is imperative to study the pathological characteristics, injury mechanisms, and therapeutic targets involved in CBS. In the present study, a CBS injury model was successfully established by injecting BV into the corneal stroma of healthy C57BL/6 mice. F-actin staining revealed corneal endothelial cell damage, decreased density, skeletal disorder, and thickened corneal stromal. The terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) assay showed apoptosis of both epithelial and endothelial cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that cytokine–cytokine interactions were the most relevant pathway for pathogenesis. Protein–protein interaction (PPI) network analysis showed that IL-1, TNF, and IL-6 were the most relevant nodes. RNA-seq after the application of Tobradex® (0.3% tobramycin and 0.1% dexamethasone) eye ointment showed that Tobradex® not only downregulated relevant inflammatory factors but also reduced corneal pain as well as promoted nerve regeneration by repairing axons. Here, a stable and reliable model of CBS injury was successfully established for the first time, and the pathogenesis of CBS and the therapeutic targets of Tobradex® are discussed. These hub genes are expected to be biomarkers and therapeutic targets for the diagnosis and treatment of CBS. Full article
(This article belongs to the Section Animal Venoms)
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21 pages, 11104 KiB  
Review
Fibrosis Is a Basement Membrane-Related Disease in the Cornea: Injury and Defective Regeneration of Basement Membranes May Underlie Fibrosis in Other Organs
by Steven E. Wilson
Cells 2022, 11(2), 309; https://doi.org/10.3390/cells11020309 - 17 Jan 2022
Cited by 21 | Viewed by 5029
Abstract
Every organ develops fibrosis that compromises functions in response to infections, injuries, or diseases. The cornea is a relatively simple, avascular organ that offers an exceptional model to better understand the pathophysiology of the fibrosis response. Injury and defective regeneration of the epithelial [...] Read more.
Every organ develops fibrosis that compromises functions in response to infections, injuries, or diseases. The cornea is a relatively simple, avascular organ that offers an exceptional model to better understand the pathophysiology of the fibrosis response. Injury and defective regeneration of the epithelial basement membrane (EBM) or the endothelial Descemet’s basement membrane (DBM) triggers the development of myofibroblasts from resident corneal fibroblasts and bone marrow-derived blood borne fibrocytes due to the increased entry of TGF beta-1/-2 into the stroma from the epithelium and tears or residual corneal endothelium and aqueous humor. The myofibroblasts, and disordered extracellular matrix these cells produce, persist until the source of injury is removed, the EBM and/or DBM are regenerated, or replaced surgically, resulting in decreased stromal TGF beta requisite for myofibroblast survival. A similar BM injury-related pathophysiology can underly the development of fibrosis in other organs such as skin and lung. The normal liver does not contain traditional BMs but develops sinusoidal endothelial BMs in many fibrotic diseases and models. However, normal hepatic stellate cells produce collagen type IV and perlecan that can modulate TGF beta localization and cognate receptor binding in the space of Dissé. BM-related fibrosis is deserving of more investigation in all organs. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Fibrosis)
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