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Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches
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Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 October 2022) | Viewed by 33145

Special Issue Editor

Prof. Dr. M. Elizabeth Fini

E-Mail Website
Guest Editor
1. New England Eye Center of Tufts Medical Center, Department of Ophthalmology, Tufts University School of Medicine, Boston, MA 02111, USA
2. Program in Pharmacology and Drug Development, Tufts Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA
Interests: eye; cornea; ocular surface; dry eye; ocular hypertension; glaucoma; matrix metalloproteinase; molecular chaperone; mucin; pathophysiology; therapeutic
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The eye is a remarkable organ of incredible functional complexity. Each of its structures, including the cornea and ocular surface, trabecular meshwork and sclera, ciliary body, iris and lens, neuroretina, and optic nerve, have their own specialized biology. These structures present problems of interest for every molecular scientist. Developmental geneticists discovered the first “master control gene” in the eye, a long-sought developmental regulator with the capacity to switch on an entire genetic program for organ formation. Neuroscientists have investigated the retina as the most accessible part of the central nervous system. Special features of the cornea have made it an important model for cell biological breakthroughs in regeneration and stem cell biology. The aqueous outflow pathways, a marvel of hydrodynamics, still hold many mysteries currently under intense investigation by molecular biologists, biophysicists, and bioengineers. This Special Issue of IJMS invites articles that provide new insights into the underlying mechanisms of diseases of the eye, as well as work on new diagnostic tools/biomarkers, and novel therapeutic strategies. Diseases include dry eye, pinguecula and pterygium, ocular hypertension, cataract, glaucoma, and retinal degeneration. Both preclinical and clinical studies with an emphasis on molecular biology approaches are of interest, and animal models of disease are encouraged.

Prof. Dr. M. Elizabeth Fini
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Eye
  • Ocular Surface
  • Cornea
  • Trabecular Meshwork
  • Sclera
  • Iris
  • Ciliary Body
  • Lens
  • Retina
  • Optic Nerve
  • Pathophysiology
  • Therapeutic

Published Papers (15 papers)

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Research

13 pages, 4546 KiB  
Article
Immune Responses to Sequential Binocular Transplantation of Allogeneic Retinal Progenitor Cells to the Vitreous Cavity in Mice
by Lu Chen, Jing Yang and Henry Klassen
Int. J. Mol. Sci. 2023, 24(7), 6205; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076205 - 25 Mar 2023
Viewed by 1291
Abstract
Intravitreal transplantation of allogeneic human retinal progenitor cells (hRPCs) holds promise as a treatment for blinding retinal degenerations. Prior work has shown that neural progenitors are well-tolerated as allografts following single injections; however, sequential delivery of allogeneic cells raises the potential risk of [...] Read more.
Intravitreal transplantation of allogeneic human retinal progenitor cells (hRPCs) holds promise as a treatment for blinding retinal degenerations. Prior work has shown that neural progenitors are well-tolerated as allografts following single injections; however, sequential delivery of allogeneic cells raises the potential risk of host sensitization with subsequent immune rejection of grafts. The current study was designed to assess whether an immune response would be induced by repeated intravitreal transplants of allogeneic RPCs utilizing the mouse animal model. We injected murine retinal progenitor cells (gmRPCs), originally derived from donors with a C57BL/6 genetic background, into BALB/c recipient mice in order to provide safety data as to what might be expected following repeated treatment of patients with allogeneic human cell product. Immune responses to gmRPCs were mild, consisting of T cells, B cells, neutrophils, and natural killer cells, with macrophages clearly the predominating. Animals treated with repeat doses of gmRPCs did not show evidence of sensitization, nor was there immune-mediated destruction of the grafts. Despite the absence of immunosuppressive treatments, allogeneic gmRPC grafts survived following repeat dosing, thus providing support for the preliminary observation that repeated injection of allogeneic RPCs to the vitreous cavity is tolerated in patients with retinitis pigmentosa. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches)
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15 pages, 2262 KiB  
Article
Dynasore Protects Corneal Epithelial Cells Subjected to Hyperosmolar Stress in an In Vitro Model of Dry Eye Epitheliopathy
by Rafael Martinez-Carrasco and M. Elizabeth Fini
Int. J. Mol. Sci. 2023, 24(5), 4754; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054754 - 01 Mar 2023
Cited by 3 | Viewed by 1322
Abstract
Epitheliopathy at the ocular surface is a defining sign of dry eye disease, a common disorder that affects 10% to 30% of the world’s population. Hyperosmolarity of the tear film is one of the main drivers of pathology, with subsequent endoplasmic reticulum (ER) [...] Read more.
Epitheliopathy at the ocular surface is a defining sign of dry eye disease, a common disorder that affects 10% to 30% of the world’s population. Hyperosmolarity of the tear film is one of the main drivers of pathology, with subsequent endoplasmic reticulum (ER) stress, the resulting unfolded protein response (UPR), and caspase-3 activation implicated in the pathway to programmed cell death. Dynasore, is a small molecule inhibitor of dynamin GTPases that has shown therapeutic effects in a variety of disease models involving oxidative stress. Recently we showed that dynasore protects corneal epithelial cells exposed to the oxidant tBHP, by selective reduction in expression of CHOP, a marker of the UPR PERK branch. Here we investigated the capacity of dynasore to protect corneal epithelial cells subjected to hyperosmotic stress (HOS). Similar to dynasore’s capacity to protect against tBHP exposure, dynasore inhibits the cell death pathway triggered by HOS, protecting against ER stress and maintaining a homeostatic level of UPR activity. However, unlike with tBHP exposure, UPR activation due to HOS is independent of PERK and mostly driven by the UPR IRE1 branch. Our results demonstrate the role of the UPR in HOS-driven damage, and the potential of dynasore as a treatment to prevent dry eye epitheliopathy. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches)
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18 pages, 34654 KiB  
Article
Recombinant Human Clusterin Seals Damage to the Ocular Surface Barrier in a Mouse Model of Ophthalmic Preservative-Induced Epitheliopathy
by Shravan K. Chintala, Jinhong Pan, Sandeep Satapathy, Rebecca Condruti, Zixuan Hao, Pei-wen Liu, Christian F. O’Conner, Joseph T. Barr, Mark R. Wilson, Shinwu Jeong and M. Elizabeth Fini
Int. J. Mol. Sci. 2023, 24(2), 981; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24020981 - 04 Jan 2023
Cited by 1 | Viewed by 1729
Abstract
There is a significant unmet need for therapeutics to treat ocular surface barrier damage, also called epitheliopathy, due to dry eye and related diseases. We recently reported that the natural tear glycoprotein CLU (clusterin), a molecular chaperone and matrix metalloproteinase inhibitor, seals and [...] Read more.
There is a significant unmet need for therapeutics to treat ocular surface barrier damage, also called epitheliopathy, due to dry eye and related diseases. We recently reported that the natural tear glycoprotein CLU (clusterin), a molecular chaperone and matrix metalloproteinase inhibitor, seals and heals epitheliopathy in mice subjected to desiccating stress in a model of aqueous-deficient/evaporative dry eye. Here we investigated CLU sealing using a second model with features of ophthalmic preservative-induced dry eye. The ocular surface was stressed by topical application of the ophthalmic preservative benzalkonium chloride (BAC). Then eyes were treated with CLU and sealing was evaluated immediately by quantification of clinical dye uptake. A commercial recombinant form of human CLU (rhCLU), as well as an rhCLU form produced in our laboratory, designed to be compatible with U.S. Food and Drug Administration guidelines on current Good Manufacturing Practices (cGMP), were as effective as natural plasma-derived human CLU (pCLU) in sealing the damaged ocular surface barrier. In contrast, two other proteins found in tears: TIMP1 and LCN1 (tear lipocalin), exhibited no sealing activity. The efficacy and selectivity of rhCLU for sealing of the damaged ocular surface epithelial barrier suggests that it could be of therapeutic value in treating BAC-induced epitheliopathy and related diseases. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches)
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14 pages, 2603 KiB  
Article
Transcriptional Profiling Provides New Insights into Organ Culture-Induced Changes in Human Donor Corneas
by Julian Wolf, Paola Kammrath Betancor, Philip Maier, Sonja Ute Heinzelmann, Jana Jiang, Clemens Lange, Thomas Reinhard, Günther Schlunck and Thabo Lapp
Int. J. Mol. Sci. 2022, 23(23), 14507; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314507 - 22 Nov 2022
Cited by 2 | Viewed by 1143
Abstract
Corneal transplantation is one of the most common forms of tissue transplantation worldwide. Donor corneal tissue used in transplantation is provided by eye banks, which store the tissue in culture medium after procurement. To date, the effects of cell culture on human corneal [...] Read more.
Corneal transplantation is one of the most common forms of tissue transplantation worldwide. Donor corneal tissue used in transplantation is provided by eye banks, which store the tissue in culture medium after procurement. To date, the effects of cell culture on human corneal tissue have not been fully elucidated. Using the 3′ RNA sequencing method for massive analysis of cDNA ends (MACE), we show that cultivation of corneal tissue leads to significant changes in a variety of molecular processes in human corneal tissue that go well beyond aspects of previously known culture effects. Functionally grouped network analysis revealed nine major groups of biological processes that were affected by corneal organ culture, among them keratinization, hypoxia, and angiogenesis, with genes from each group being affected by culture time. A cell type deconvolution analysis revealed significant modulations of the corneal immune cell profile in a time dependent manner. The results suggest that current culture conditions should be further refined and that prolonged cultivation may be detrimental. Recently, we showed that MACE enables transcriptional profiling of formalin-fixed and paraffin-embedded (FFPE) conjunctival tissue with high accuracy even after more than 10 years of storage. Here we demonstrate that MACE provides comparable results for native and FFPE corneal tissue, confirming that the technology is suitable for transcriptome analysis of a wide range of archived diseased corneal samples stored in histological archives. Finally, our data underscore the feasibility of bioinformatics cell-type enrichment analysis in bulk RNA-seq data to profile immune cell composition in fixed and archived corneal tissue samples, for which RNA-seq analysis of individual cells is often not possible. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches)
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12 pages, 2153 KiB  
Article
Recombinant Human Proteoglycan 4 (rhPRG4) Downregulates TNFα-Stimulated NFκB Activity and FAT10 Expression in Human Corneal Epithelial Cells
by Nikhil G. Menon, Yasir Suhail, Ruchi Goyal, Wenqiang Du, Adam P. Tanguay, Gregory D. Jay, Mallika Ghosh, Kshitiz and Tannin A. Schmidt
Int. J. Mol. Sci. 2022, 23(21), 12711; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112711 - 22 Oct 2022
Cited by 3 | Viewed by 1290
Abstract
Dry Eye Disease (DED) is a complex pathology affecting millions of people with significant impact on quality of life. Corneal inflammation, including via the nuclear factor kappa B (NFκB) pathway, plays a key etiological role in DED. Recombinant human proteoglycan 4 (rhPRG4) has [...] Read more.
Dry Eye Disease (DED) is a complex pathology affecting millions of people with significant impact on quality of life. Corneal inflammation, including via the nuclear factor kappa B (NFκB) pathway, plays a key etiological role in DED. Recombinant human proteoglycan 4 (rhPRG4) has been shown to be a clinically effective treatment for DED that has anti-inflammatory effects in corneal epithelial cells, but the underlying mechanism is still not understood. Our goal was to understand if rhPRG4 affects tumor necrosis factor α (TNFα)-stimulated inflammatory activity in corneal epithelial cells. We treated hTERT-immortalized corneal epithelial (hTCEpi) cells ± TNFα ± rhPRG4 and performed Western blotting on cell lysate and RNA sequencing. Bioinformatics analysis revealed that rhPRG4 had a significant effect on TNFα-mediated inflammation with potential effects on matricellular homeostasis. rhPRG4 reduced activation of key inflammatory pathways and decreased expression of transcripts for key inflammatory cytokines, interferons, interleukins, and transcription factors. TNFα treatment significantly increased phosphorylation and nuclear translocation of p65, and rhPRG4 significantly reduced both these effects. RNA sequencing identified human leukocyte antigen (HLA)-F adjacent transcript 10 (FAT10), a ubiquitin-like modifier protein which has not been studied in the context of DED, as a key pro-inflammatory transcript increased by TNFα and decreased by rhPRG4. These results were confirmed at the protein level. In summary, rhPRG4 is able to downregulate NFκB activity in hTCEpi cells, suggesting a potential biological mechanism by which it may act as a therapeutic for DED. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches)
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26 pages, 6350 KiB  
Article
Dysregulated Retinoic Acid Signaling in the Pathogenesis of Pseudoexfoliation Syndrome
by Matthias Zenkel, Ursula Hoja, Andreas Gießl, Daniel Berner, Bettina Hohberger, Julia M. Weller, Loretta König, Lisa Hübner, Thomas A. Ostermann, Gabriele C. Gusek-Schneider, Friedrich E. Kruse, Francesca Pasutto and Ursula Schlötzer-Schrehardt
Int. J. Mol. Sci. 2022, 23(11), 5977; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23115977 - 26 May 2022
Cited by 8 | Viewed by 2009
Abstract
Pseudoexfoliation (PEX) syndrome, a stress-induced fibrotic matrix process, is the most common recognizable cause of open-angle glaucoma worldwide. The recent identification of PEX-associated gene variants uncovered the vitamin A metabolic pathway as a factor influencing the risk of disease. In this study, we [...] Read more.
Pseudoexfoliation (PEX) syndrome, a stress-induced fibrotic matrix process, is the most common recognizable cause of open-angle glaucoma worldwide. The recent identification of PEX-associated gene variants uncovered the vitamin A metabolic pathway as a factor influencing the risk of disease. In this study, we analyzed the role of the retinoic acid (RA) signaling pathway in the PEX-associated matrix metabolism and evaluated its targeting as a potential candidate for an anti-fibrotic intervention. We provided evidence that decreased expression levels of RA pathway components and diminished RA signaling activity occur in an antagonistic crosstalk with TGF-β1/Smad signaling in ocular tissues and cells from PEX patients when compared with age-matched controls. Genetic and pharmacologic modes of RA pathway inhibition induced the expression and production of PEX-associated matrix components by disease-relevant cell culture models in vitro. Conversely, RA signaling pathway activation by natural and synthetic retinoids was able to suppress PEX-associated matrix production and formation of microfibrillar networks via antagonization of Smad-dependent TGF-β1 signaling. The findings indicate that deficient RA signaling in conjunction with hyperactivated TGF-β1/Smad signaling is a driver of PEX-associated fibrosis, and that restoration of RA signaling may be a promising strategy for anti-fibrotic intervention in patients with PEX syndrome and glaucoma. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches)
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14 pages, 1968 KiB  
Article
SOX2 Is a Univocal Marker for Human Oral Mucosa Epithelium Useful in Post-COMET Patient Characterization
by Eustachio Attico, Giulia Galaverni, Elisa Bianchi, Lorena Losi, Rossella Manfredini, Alessandro Lambiase, Paolo Rama and Graziella Pellegrini
Int. J. Mol. Sci. 2022, 23(10), 5785; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105785 - 21 May 2022
Cited by 3 | Viewed by 2464
Abstract
Total bilateral Limbal Stem Cells Deficiency is a pathologic condition of the ocular surface due to loss or impairment of corneal stem cell function, altering homeostasis of the corneal epithelium. Cultivated Oral Mucosa Epithelial Transplantation (COMET) is the only autologous treatment for this [...] Read more.
Total bilateral Limbal Stem Cells Deficiency is a pathologic condition of the ocular surface due to loss or impairment of corneal stem cell function, altering homeostasis of the corneal epithelium. Cultivated Oral Mucosa Epithelial Transplantation (COMET) is the only autologous treatment for this pathology. During the follow-up, a proper characterization of the transplanted oral mucosa on the ocular surface supports understanding the regenerative process. The previously proposed markers for oral mucosa identification (e.g., keratins 3 and 13) are co-expressed by corneal and conjunctival epithelia. Here, we propose a new specific marker to distinguish human oral mucosa from the epithelia of the ocular surface. We compared the transcriptome of holoclones (stem cells) from the human oral mucosa, limbal and conjunctival cultures by microarray assay. High expression of SOX2 identified the oral mucosa vs. cornea and conjunctiva, while PAX6 was highly expressed in corneal and conjunctival epithelia. The transcripts were validated by qPCR, and immunological methods identified the related proteins. Finally, the proposed markers were used to analyze a 10-year follow-up aniridic patient treated by COMET. These findings will support the follow-up analysis of COMET treated patients and help to shed light on the mechanism of corneal repair and regeneration. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches)
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15 pages, 2624 KiB  
Article
CD47 Binding on Vascular Endothelial Cells Inhibits IL-17-Mediated Leukocyte Adhesion
by Laura Soriano-Romaní, Fayaz A. Mir, Niharika Singh, Ian Chin, Ali Hafezi-Moghadam and Sharmila Masli
Int. J. Mol. Sci. 2022, 23(10), 5705; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105705 - 20 May 2022
Cited by 2 | Viewed by 1925
Abstract
To address the conflicting role of thrombospondin (TSP)-1 reported in acute and chronic pathologies, this study investigated the role of TSP-1 in regulating leukocyte recruitment and regulation of VCAM-1 expression using mouse models of uveitis. The spontaneously increased VCAM-1 expression and leukocyte adhesion [...] Read more.
To address the conflicting role of thrombospondin (TSP)-1 reported in acute and chronic pathologies, this study investigated the role of TSP-1 in regulating leukocyte recruitment and regulation of VCAM-1 expression using mouse models of uveitis. The spontaneously increased VCAM-1 expression and leukocyte adhesion in retinas of TSP-1-deficient mice suggested a TSP-1-mediated regulation of VCAM-1 expression. In a chronic uveitis model, induced by immunizing wild-type mice with specific interphotoreceptor retinoid-binding protein (IRBP) peptide, topically applied TSP-1-derived CD47-binding peptide significantly reduced the clinical disease course and retinal leukocyte adhesion as compared to the control peptide-treated group. In contrast, in LPS-mediated acute uveitis, TSP-1 deficiency significantly reduced the retinal leukocyte adhesion. The results of our in vitro study, using vascular endothelial cell (EC) cultures, demonstrate that unlike TNF-α, VCAM-1 expression induced by IL-17 is associated with a reduced expression of endogenous TSP-1. Such reduced endogenous TSP-1 expression in IL-17-stimulated ECs helps limit the CD36-mediated increased VCAM-1 expression, while favoring CD47-mediated inhibition of VCAM-1 expression and leukocyte adhesion. Thus, our study identifies TSP-1:CD47 interaction as a molecular pathway that modulates IL-17-mediated VCAM-1 expression, contributing to its anti-inflammatory effect in chronic inflammatory conditions. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches)
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13 pages, 2369 KiB  
Article
Alleviation of Endoplasmic Reticulum Stress Enhances Human Corneal Epithelial Cell Viability under Hyperosmotic Conditions
by Damien Guindolet, Ashley M. Woodward, Eric E. Gabison and Pablo Argüeso
Int. J. Mol. Sci. 2022, 23(9), 4528; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094528 - 20 Apr 2022
Cited by 5 | Viewed by 1831
Abstract
Tear hyperosmolarity plays an essential role in the initiation and progression of dry-eye disease. Under a hyperosmotic environment, corneal epithelial cells experience perturbations in endoplasmic reticulum function that can lead to proinflammatory signaling and apoptosis. In this study, we investigated the effect of [...] Read more.
Tear hyperosmolarity plays an essential role in the initiation and progression of dry-eye disease. Under a hyperosmotic environment, corneal epithelial cells experience perturbations in endoplasmic reticulum function that can lead to proinflammatory signaling and apoptosis. In this study, we investigated the effect of tauroursodeoxycholic acid (TUDCA), a chemical chaperone known to protect against endoplasmic reticulum stress, on corneal epithelial cells exposed to hyperosmotic conditions. We found that the expression of the genes involved in the activation of the unfolded protein response and the pro-apoptotic transcription factor DDIT3 were markedly upregulated in patients with Sjögren’s dry-eye disease and in a human model of corneal epithelial differentiation following treatment with hyperosmotic saline. Experiments in vitro demonstrated that TUDCA prevented hyperosmotically induced cell death by reducing nuclear DNA fragmentation and caspase-3 activation. TUDCA supplementation also led to the transcriptional repression of CXCL8 and IL5, two inflammatory mediators associated with dry-eye pathogenesis. These studies highlight the role of hyperosmotic conditions in promoting endoplasmic reticulum stress in the cornea and identify TUDCA as a potential therapeutic agent for the treatment of dry-eye disease. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches)
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17 pages, 3512 KiB  
Article
Unravelling Novel Roles of Salivary Exosomes in the Regulation of Human Corneal Stromal Cell Migration and Wound Healing
by Paulina Escandon, Angela Liu, Sarah E. Nicholas, Asher Khan, Kamran M. Riaz and Dimitrios Karamichos
Int. J. Mol. Sci. 2022, 23(8), 4330; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084330 - 14 Apr 2022
Cited by 11 | Viewed by 2198
Abstract
Salivary exosomes have demonstrated vast therapeutic and diagnostic potential in numerous diseases. This study pioneers previously unexplored roles of SE in the context of corneal wound healing by utilizing primary corneal stromal cells from healthy (HCFs), type I diabetes mellitus (T1DMs), type II [...] Read more.
Salivary exosomes have demonstrated vast therapeutic and diagnostic potential in numerous diseases. This study pioneers previously unexplored roles of SE in the context of corneal wound healing by utilizing primary corneal stromal cells from healthy (HCFs), type I diabetes mellitus (T1DMs), type II DM (T2DMs), and keratoconus (HKCs) subjects. Purified, healthy human SEs carrying tetraspanins CD9+, CD63+, and CD81+ were utilized. Scratch and cell migration assays were performed after 0, 6, 12, 24, and 48 h following SE stimulation (5 and 25 µg/mL). Significantly slower wound closure was observed at 6 and 12 h in HCFs with 5 μg/mL SE and T1DMs with 5 and 25 μg/mL SE. All wounds were closed by 24-hour, post-wounding. HKCs, T1DMs, and T2DMs with 25µg/mL SE exhibited a significant upregulation of cleaved vimentin compared to controls. Thrombospondin 1 was significantly upregulated in HCFs, HKCs, and T2DMs with 25 µg/mL SE. Lastly, HKCs, T1DMs, and T2DMs exhibited a significant downregulation of fibronectin with 25 μg/mL SE. Whether SEs can be utilized to clinical settings in restoring corneal defects is unknown. This is the first-ever study exploring the role of SEs in corneal wound healing. While the sample size was small, results are highly novel and provide a strong foundation for future studies. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches)
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24 pages, 4000 KiB  
Article
IGFBP-3 Regulates Mitochondrial Hyperfusion and Metabolic Activity in Ocular Surface Epithelia during Hyperosmolar Stress
by Whitney L. Stuard, Melis K. Guner and Danielle M. Robertson
Int. J. Mol. Sci. 2022, 23(7), 4066; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23074066 - 06 Apr 2022
Cited by 3 | Viewed by 2970
Abstract
In the eye, hyperosmolarity of the precorneal tear film triggers inflammation and the development of dry eye disease (DED), a highly prevalent condition that causes depression and disability in severe forms. A member of the insulin-like growth factor (IGF) family, the IGF binding [...] Read more.
In the eye, hyperosmolarity of the precorneal tear film triggers inflammation and the development of dry eye disease (DED), a highly prevalent condition that causes depression and disability in severe forms. A member of the insulin-like growth factor (IGF) family, the IGF binding protein-3 (IGFBP-3), is a pleiotropic protein with known roles in growth downregulation and survival. IGFBP-3 exerts these effects by blocking IGF-1 activation of the type 1 IGF-receptor (IGF-1R). Here, we examined a new IGF-independent role for IGFBP-3 in the regulation of mitochondrial and metabolic activity in ocular surface epithelial cells subject to hyperosmolar stress and in a mouse model of DED. We found that hyperosmolar stress decreased IGFBP-3 expression in vitro and in vivo. Treatment with exogenous IGFBP-3 induced an early, transient shift in IGF-1R to mitochondria, followed by IGFBP-3 nuclear accumulation. IGFBP-3 nuclear accumulation increased protein translation, blocked the hyperosmolar-mediated decrease in oxidative phosphorylation through the induction of mitochondrial hyperfusion, and restored corneal health in vivo. These data indicate that IGFBP-3 acts a stress response protein in ocular surface epithelia subject to hyperosmolar stress. These findings may lead to the development of first-in-class therapeutics to treat eye diseases with underlying mitochondrial dysfunction. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches)
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17 pages, 5635 KiB  
Article
Dysfunctional cGMP Signaling Leads to Age-Related Retinal Vascular Alterations and Astrocyte Remodeling in Mice
by Joseph M. Holden, Sara Al Hussein Al Awamlh, Louis-Philippe Croteau, Andrew M. Boal, Tonia S. Rex, Michael L. Risner, David J. Calkins and Lauren K. Wareham
Int. J. Mol. Sci. 2022, 23(6), 3066; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063066 - 12 Mar 2022
Cited by 6 | Viewed by 2293
Abstract
The nitric oxide–guanylyl cyclase-1–cyclic guanylate monophosphate (NO–GC-1–cGMP) pathway is integral to the control of vascular tone and morphology. Mice lacking the alpha catalytic domain of guanylate cyclase (GC1−/−) develop retinal ganglion cell (RGC) degeneration with age, with only modest fluctuations [...] Read more.
The nitric oxide–guanylyl cyclase-1–cyclic guanylate monophosphate (NO–GC-1–cGMP) pathway is integral to the control of vascular tone and morphology. Mice lacking the alpha catalytic domain of guanylate cyclase (GC1−/−) develop retinal ganglion cell (RGC) degeneration with age, with only modest fluctuations in intraocular pressure (IOP). Increasing the bioavailability of cGMP in GC1−/− mice prevents neurodegeneration independently of IOP, suggesting alternative mechanisms of retinal neurodegeneration. In continuation to these studies, we explored the hypothesis that dysfunctional cGMP signaling leads to changes in the neurovascular unit that may contribute to RGC degeneration. We assessed retinal vasculature and astrocyte morphology in young and aged GC1−/− and wild type mice. GC1−/− mice exhibit increased peripheral retinal vessel dilation and shorter retinal vessel branching with increasing age compared to Wt mice. Astrocyte cell morphology is aberrant, and glial fibrillary acidic protein (GFAP) density is increased in young and aged GC1−/− mice, with areas of dense astrocyte matting around blood vessels. Our results suggest that proper cGMP signaling is essential to retinal vessel morphology with increasing age. Vascular changed are preceded by alterations in astrocyte morphology which may together contribute to retinal neurodegeneration and loss of visual acuity observed in GC1−/− mice. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches)
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12 pages, 1576 KiB  
Article
Intraocular Delivery of a Collagen Mimetic Peptide Repairs Retinal Ganglion Cell Axons in Chronic and Acute Injury Models
by Marcio Ribeiro, Nolan R. McGrady, Robert O. Baratta, Brian J. Del Buono, Eric Schlumpf and David J. Calkins
Int. J. Mol. Sci. 2022, 23(6), 2911; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23062911 - 08 Mar 2022
Cited by 7 | Viewed by 3058
Abstract
Vision loss through the degeneration of retinal ganglion cell (RGC) axons occurs in both chronic and acute conditions that target the optic nerve. These include glaucoma, in which sensitivity to intraocular pressure (IOP) causes early RGC axonal dysfunction, and optic nerve trauma, which [...] Read more.
Vision loss through the degeneration of retinal ganglion cell (RGC) axons occurs in both chronic and acute conditions that target the optic nerve. These include glaucoma, in which sensitivity to intraocular pressure (IOP) causes early RGC axonal dysfunction, and optic nerve trauma, which causes rapid axon degeneration from the site of injury. In each case, degeneration is irreversible, necessitating new therapeutics that protect, repair, and regenerate RGC axons. Recently, we demonstrated the reparative capacity of using collagen mimetic peptides (CMPs) to heal fragmented collagen in the neuronal extracellular milieu. This was an important step in the development of neuronal-based therapies since neurodegeneration involves matrix metalloproteinase (MMP)-mediated remodeling of the collagen-rich environment in which neurons and their axons exist. We found that intraocular delivery of a CMP comprising single-strand fractions of triple helix human type I collagen prevented early RGC axon dysfunction in an inducible glaucoma model. Additionally, CMPs also promoted neurite outgrowth from dorsal root ganglia, challenged in vitro by partial digestion of collagen. Here, we compared the ability of a CMP sequence to protect RGC axons in both inducible glaucoma and optic nerve crush. A three-week +40% elevation in IOP caused a 67% degradation in anterograde transport to the superior colliculus, the primary retinal projection target in rodents. We found that a single intravitreal injection of CMP during the period of IOP elevation significantly reduced this degradation. The same CMP delivered shortly after optic nerve crush promoted significant axonal recovery during the two-week period following injury. Together, these findings support a novel protective and reparative role for the use of CMPs in both chronic and acute conditions affecting the survival of RGC axons in the optic projection to the brain. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches)
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18 pages, 3197 KiB  
Article
The Role of Estriol and Estrone in Keratoconic Stromal Sex Hormone Receptors
by Paulina Escandon, Sarah E. Nicholas, Rebecca L. Cunningham, David A. Murphy, Kamran M. Riaz and Dimitrios Karamichos
Int. J. Mol. Sci. 2022, 23(2), 916; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020916 - 14 Jan 2022
Cited by 15 | Viewed by 1843
Abstract
Keratoconus (KC) is a progressive corneal thinning disease that manifests in puberty and worsens during pregnancy. KC onset and progression are attributed to diverse factors that include: environmental, genetics, and hormonal imbalances; however, the pathobiology remains elusive. This study aims to determine the [...] Read more.
Keratoconus (KC) is a progressive corneal thinning disease that manifests in puberty and worsens during pregnancy. KC onset and progression are attributed to diverse factors that include: environmental, genetics, and hormonal imbalances; however, the pathobiology remains elusive. This study aims to determine the role of corneal stroma sex hormone receptors in KC and their interplay with estrone (E1) and estriol (E3) using our established 3D in vitro model. Healthy cornea stromal cells (HCFs) and KC cornea stromal cells (HKCs), both male and female, were stimulated with various concentrations of E1 and E3. Significant changes were observed between cell types, as well as between males and females in the sex hormone receptors tested; androgen receptor (AR), progesterone receptor (PR), estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ) using Western blot analysis. E1 and E3 stimulations in HCF females showed AR, PR, and ERβ were significantly upregulated compared to HCF males. In contrast, ERα and ERβ had significantly higher expression in HKC’s females than HKC’s males. Our data suggest that the human cornea is a sex-dependent, hormone-responsive tissue that is significantly influenced by E1 and E3. Therefore, it is plausible that E1, E3, and sex hormone receptors are involved in the KC pathobiology, warranting further investigation. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches)
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29 pages, 661 KiB  
Article
Transcriptome Analysis of Pterygium and Pinguecula Reveals Evidence of Genomic Instability Associated with Chronic Inflammation
by María Fernanda Suarez, José Echenique, Juan Manuel López, Esteban Medina, Mariano Irós, Horacio M. Serra and M. Elizabeth Fini
Int. J. Mol. Sci. 2021, 22(21), 12090; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222112090 - 08 Nov 2021
Cited by 7 | Viewed by 4147
Abstract
Solar damage due to ultraviolet radiation (UVR) is implicated in the development of two proliferative lesions of the ocular surface: pterygium and pinguecula. Pterygium and pinguecula specimens were collected, along with adjacent healthy conjunctiva specimens. RNA was extracted and sequenced. Pairwise comparisons were [...] Read more.
Solar damage due to ultraviolet radiation (UVR) is implicated in the development of two proliferative lesions of the ocular surface: pterygium and pinguecula. Pterygium and pinguecula specimens were collected, along with adjacent healthy conjunctiva specimens. RNA was extracted and sequenced. Pairwise comparisons were made of differentially expressed genes (DEGs). Computational methods were used for analysis. Transcripts from 18,630 genes were identified. Comparison of two subgroups of pterygium specimens uncovered evidence of genomic instability associated with inflammation and the immune response; these changes were also observed in pinguecula, but to a lesser extent. Among the top DEGs were four genes encoding tumor suppressors that were downregulated in pterygium: C10orf90, RARRES1, DMBT1 and SCGB3A1; C10orf90 and RARRES1 were also downregulated in pinguecula. Ingenuity Pathway Analysis overwhelmingly linked DEGs to cancer for both lesions; however, both lesions are clearly still benign, as evidenced by the expression of other genes indicating their well-differentiated and non-invasive character. Pathways for epithelial cell proliferation were identified that distinguish the two lesions, as well as genes encoding specific pathway components. Upregulated DEGs common to both lesions, including KRT9 and TRPV3, provide a further insight into pathophysiology. Our findings suggest that pterygium and pinguecula, while benign lesions, are both on the pathological pathway towards neoplastic transformation. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches)
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