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Cell Biology of the Cornea and Ocular Surface

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Tissues and Organs".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 13786

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Special Issue Editors

Dr. W. Matthew Petroll

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Guest Editor

The University of Texas Southwestern Medical Center, Dallas, TX, USA
Interests: corneal cell and tissue mechanics; corneal wound healing; corneal imaging; tissue engineering

Dr. Danielle M. Robertson

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Guest Editor

The University of Texas Southwestern Medical Center, Dallas, TX, USA
Interests: corneal epithelial cell biology; mitochondrial physiology; metabolism; autophagy; infection

Special Issue Information

Dear Colleagues,

The cornea is an optically clear tissue that forms the front surface of the eye, accounting for nearly two-thirds of the eye’s refractive power. Proper vision is dependent on the shape, structure and transparency of the cornea, as well as the composition and stability of the tear film. The goal of this Special Issue is to highlight recent advances in understanding the underlying cellular mechanisms that regulate the structure and function of the cornea and ocular surface.

We welcome original research and review articles on the following topics in relation to health and disease and responses to injury or surgery: cellular signaling, molecular biology, cell–extracellular matrix interactions, immunology, metabolism and mechanobiology. Specific areas of interest include but are not limited to: (1) homeostasis of the normal cornea and ocular surface; (2) the pathogenesis and treatment of dry eye disease, diabetes, infectious keratitis and keratoconus; and (3) the response to corneal injury, refractive surgery, keratoplasty and UV corneal cross-linking.

Dr. W. Matthew Petroll
Dr. Danielle M. Robertson
Guest Editors

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Keywords

cornea
ocular surface
wound healing
inflammation
adhesion
signal transduction

Published Papers (10 papers)

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19 pages, 11010 KiB

Open AccessArticle

Aberrations in Cell Signaling Quantified in Diabetic Murine Globes after Injury

by Nicholas A. Azzari, Kristen L. Segars, Srikar Rapaka, Landon Kushimi, Celeste B. Rich and Vickery Trinkaus-Randall

Cells 2024, 13(1), 26; https://doi.org/10.3390/cells13010026 - 21 Dec 2023

Cited by 1 | Viewed by 946

Abstract

The corneal epithelium is an avascular structure that has a unique wound healing mechanism, which allows for rapid wound closure without compromising vision. This wound healing mechanism is attenuated in diabetic patients, resulting in poor clinical outcomes and recurrent non-healing erosion. We investigated changes in cellular calcium signaling activity during the wound response in murine diabetic tissue using live cell imaging from both ex vivo and in vitro models. The calcium signaling propagation in diabetic cells was significantly decreased and displayed altered patterns compared to non-diabetic controls. Diabetic cells and tissue display distinct expression of the purinergic receptor, P2X7, which mediates the wound healing response. We speculate that alterations in P2X7 expression, interactions with other proteins, and calcium signaling activity significantly impact the wound healing response. This may explain aberrations in the diabetic wound response. Full article

(This article belongs to the Special Issue Cell Biology of the Cornea and Ocular Surface)

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10 pages, 1195 KiB

Open AccessCommunication

Characterization of Cell Surface Glycan Profiles in Human and Mouse Corneas Using Lectin Microarrays

by Rafael Martínez-Carrasco and Pablo Argüeso

Cells 2023, 12(19), 2356; https://doi.org/10.3390/cells12192356 - 26 Sep 2023

Viewed by 1002

Abstract

The advent of high-throughput sequencing technologies has facilitated the profiling of glycosylation genes at a single-cell level in complex biological systems, but the significance of these gene signatures to the composition of the glycocalyx remains ambiguous. Here, we used lectin microarrays to characterize the composition of cell surface glycans in human and mouse corneas and determine its relationship to single-cell transcriptomic data. Our results identify a series of cell surface glycan signatures that are unique to the different cell types of the human cornea and that correlate, to a certain extent, with the transcriptional expression of glycosylation genes. These include pathways involved in the biosynthesis of O-glycans in epithelial cells and core fucose on stromal and endothelial cell surfaces. Moreover, we show that human and mouse corneas display some structural differences in terms of cell surface glycan composition. These results could provide insights into the specialized function of individual cell types in the cornea and foster the identification of novel cornea-specific biomarkers. Full article

(This article belongs to the Special Issue Cell Biology of the Cornea and Ocular Surface)

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13 pages, 5931 KiB

Open AccessArticle

Cell–Cell and Cell–Matrix Interactions at the Presumptive Stem Cell Niche of the Chick Corneal Limbus

by Kiranjit K. Bains, Robert D. Young, Elena Koudouna, Philip N. Lewis and Andrew J. Quantock

Cells 2023, 12(19), 2334; https://doi.org/10.3390/cells12192334 - 22 Sep 2023

Cited by 1 | Viewed by 796

Abstract

(1) Background: Owing to its ready availability and ease of acquisition, developing chick corneal tissue has long been used for research purposes. Here, we seek to ascertain the three-dimensional microanatomy and spatiotemporal interrelationships of the cells (epithelial and stromal), extracellular matrix, and vasculature at the corneo-scleral limbus as the site of the corneal stem cell niche of the chicken eye. (2) Methods: The limbus of developing (i.e., embryonic days (E) 16 and 18, just prior to hatch) and mature chicken eyes was imaged using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and the volume electron microscopy technique, serial-block face SEM (SBF-SEM), the latter technique allowing us to generate three-dimensional reconstructions from data sets of up to 1000 serial images; (3) Results: Data revealed that miniature limbal undulations of the embryonic basement membrane, akin to Palisades of Vogt (PoV), matured into distinct invaginations of epithelial cells that extended proximally into a vascularized limbal stroma. Basal limbal epithelial cells, moreover, occasionally exhibited a high nuclear:cytoplasmic ratio, which is a characteristic feature of stem cells. SBF-SEM identified direct cell–cell associations between corneal epithelial and stromal cells at the base of structures akin to limbal crypts (LCs), with cord-like projections of extracellular matrix extending from the basal epithelial lamina into the subjacent stroma, where they made direct contact with stomal cells in the immature limbus. (4) Conclusion: Similarities with human tissue suggest that the corneal limbus of the mature chicken eye is likely the site of a corneal stem cell niche. The ability to study embryonic corneas pre-hatch, where we see characteristic niche-like features emerge, thus provides an opportunity to chart the development of the limbal stem cell niche of the cornea. Full article

(This article belongs to the Special Issue Cell Biology of the Cornea and Ocular Surface)

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18 pages, 4763 KiB

Open AccessArticle

Opposing Roles of Blood-Borne Monocytes and Tissue-Resident Macrophages in Limbal Stem Cell Damage after Ocular Injury

by Chengxin Zhou, Fengyang Lei, Mirja Mittermaier, Bruce Ksander, Reza Dana, Claes H. Dohlman, Demetrios G. Vavvas, James Chodosh and Eleftherios I. Paschalis

Cells 2023, 12(16), 2089; https://doi.org/10.3390/cells12162089 - 18 Aug 2023

Cited by 1 | Viewed by 1038

Abstract

Limbal stem cell (LSC) deficiency is a frequent and severe complication after chemical injury to the eye. Previous studies have assumed this is mediated directly by the caustic agent. Here we show that LSC damage occurs through immune cell mediators, even without direct injury to LSCs. In particular, pH elevation in the anterior chamber (AC) causes acute uveal stress, the release of inflammatory cytokines at the basal limbal tissue, and subsequent LSC damage and death. Peripheral C-C chemokine receptor type 2 positive/CX3C motif chemokine receptor 1 negative (CCR2⁺ CX3CR1⁻) monocytes are the key mediators of LSC damage through the upregulation of tumor necrosis factor-alpha (TNF-α) at the limbus. In contrast to peripherally derived monocytes, CX3CR1⁺ CCR2⁻ tissue-resident macrophages have a protective role, and their depletion prior to injury exacerbates LSC loss and increases LSC vulnerability to TNF-α-mediated apoptosis independently of CCR2⁺ cell infiltration into the tissue. Consistently, repopulation of the tissue by new resident macrophages not only restores the protective M2-like phenotype of macrophages but also suppresses LSC loss after exposure to inflammatory signals. These findings may have clinical implications in patients with LSC loss after chemical burns or due to other inflammatory conditions. Full article

(This article belongs to the Special Issue Cell Biology of the Cornea and Ocular Surface)

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12 pages, 4051 KiB

Open AccessArticle

Interleukin-36 Receptor Signaling Attenuates Epithelial Wound Healing in C57BL/6 Mouse Corneas

by Qi Chen, Nan Gao and Fu-Shin Yu

Cells 2023, 12(12), 1587; https://doi.org/10.3390/cells12121587 - 8 Jun 2023

Viewed by 1279

Abstract

The IL-36 cytokines are known to play various roles in mediating the immune and inflammatory response to tissue injury in a context-dependent manner. This study investigated the role of IL-36R signaling in mediating epithelial wound healing in normal (NL) and diabetic (DM) C57BL/6 mouse corneas. The rate of epithelial wound closure was significantly accelerated in IL-36 receptor-deficient (IL-36R^−/−) compared to wild-type (WT) mice. Wounding increased IL-36α and -36γ but repressed IL-36R antagonist (IL-36Ra) expression in B6 mouse corneal epithelial cells. The wound-induced proinflammatory cytokines CXCL1 and CXCL2 were dampened, while the antimicrobial peptides (AMPs) S100A8 and A9 were augmented in IL-36R^−/− mouse corneas. Intriguingly, the expression of AMP LCN2 was augmented at the mRNA level. LCN2 deficiency resulted in an acceleration of epithelial wound healing. IL-36R deficiency also greatly increased the healing rate of the corneal epithelial wound in DM mice. IL-36R deficiency also suppressed IL-1β, IL-1Ra, and ICAM expression in unwounded-DM mice and wounded NL corneas. Opposing IL-1β and ICAM, the expression of IL-Ra in DM corneas of IL-36R^−/− mice was augmented. The presence of recombinant IL-1Ra and IL-36Ra accelerated epithelial wound closure in T1DM corneas of B6 mice. Our study revealed an unprecedented role of IL-36R signaling in controlling corneal epithelial wound healing in normal (NL) and diabetic (DM) mice. Our data suggest that IL-36Ra, similar to IL-1Ra, might be a therapeutic reagent for improving wound healing and reducing wound-associated ulceration, particularly in the cornea and potentially in the skin of DM patients. Full article

(This article belongs to the Special Issue Cell Biology of the Cornea and Ocular Surface)

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15 pages, 4022 KiB

Open AccessArticle

Mustard Gas Exposure Actuates SMAD2/3 Signaling to Promote Myofibroblast Generation in the Cornea

by Nishant R. Sinha, Ratnakar Tripathi, Praveen K. Balne, Laila Suleiman, Katherine Simkins, Shyam S. Chaurasia and Rajiv R. Mohan

Cells 2023, 12(11), 1533; https://doi.org/10.3390/cells12111533 - 2 Jun 2023

Cited by 2 | Viewed by 1493

Abstract

Sulfur mustard gas (SM) is a vesicating and alkylating agent used as a chemical weapon in many mass-casualty incidents since World War I. Ocular injuries were reported in >90% of exposed victims. The mechanisms underlying SM-induced blindness remain elusive. This study tested the hypothesis that SM-induced corneal fibrosis occurs due to the generation of myofibroblasts from resident fibroblasts via the SMAD2/3 signaling pathway in rabbit eyes in vivo and primary human corneal fibroblasts (hCSFs) isolated from donor corneas in vitro. Fifty-four New Zealand White Rabbits were divided into three groups (Naïve, Vehicle, SM-Vapor treated). The SM-Vapor group was exposed to SM at 200 mg-min/m3 for 8 min at the MRI Global facility. Rabbit corneas were collected on day 3, day 7, and day 14 for immunohistochemistry, RNA, and protein lysates. SM caused a significant increase in SMAD2/3, pSMAD, and ɑSMA expression on day 3, day 7, and day 14 in rabbit corneas. For mechanistic studies, hCSFs were treated with nitrogen mustard (NM) or NM + SIS3 (SMAD3-specific inhibitor) and collected at 30 m, 8 h, 24 h, 48 h, and 72 h. NM significantly increased TGFβ, pSMAD3, and SMAD2/3 levels. On the contrary, inhibition of SMAD2/3 signaling by SIS3 treatment significantly reduced SMAD2/3, pSMAD3, and ɑSMA expression in hCSFs. We conclude that SMAD2/3 signaling appears to play a vital role in myofibroblast formation in the cornea following mustard gas exposure. Full article

(This article belongs to the Special Issue Cell Biology of the Cornea and Ocular Surface)

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17 pages, 13240 KiB

Open AccessArticle

Corneal Edema in Inducible Slc4a11 Knockout Is Initiated by Mitochondrial Superoxide Induced Src Kinase Activation

by Diego G. Ogando, Edward T. Kim, Shimin Li and Joseph A. Bonanno

Cells 2023, 12(11), 1528; https://doi.org/10.3390/cells12111528 - 1 Jun 2023

Cited by 1 | Viewed by 1558

Abstract

Purpose: Inducible Slc4a11 KO leads to corneal edema by disruption of the pump and barrier functions of the corneal endothelium (CE). The loss of Slc4a11 NH₃-activated mitochondrial uncoupling leads to mitochondrial membrane potential hyperpolarization-induced oxidative stress. The goal of this study was to investigate the link between oxidative stress and the failure of pump and barrier functions and to test different approaches to revert the process. Methods: Mice which were homozygous for Slc4a11 Flox and Estrogen receptor –Cre Recombinase fusion protein alleles at 8 weeks of age were fed Tamoxifen (Tm)-enriched chow (0.4 g/Kg) for 2 weeks, and controls were fed normal chow. During the initial 14 days, Slc4a11 expression, corneal thickness (CT), stromal [lactate], Na⁺-K⁺ ATPase activity, mitochondrial superoxide levels, expression of lactate transporters, and activity of key kinases were assessed. In addition, barrier function was assessed by fluorescein permeability, ZO-1 tight junction integrity, and cortical cytoskeleton F-actin morphology. Results: Tm induced a rapid decay in Slc4a11 expression that was 84% complete at 7 days and 96% complete at 14 days of treatment. Superoxide levels increased significantly by day 7; CT and fluorescein permeability by day 14. Tight junction ZO-1 distribution and the cortical cytoskeleton were disrupted at day 14, concomitant with decreased expression of Cldn1, yet with increased tyrosine phosphorylation. Stromal lactate increased by 60%, Na⁺-K⁺ ATPase activity decreased by 40%, and expression of lactate transporters MCT2 and MCT4 significantly decreased, but MCT1 was unchanged at 14 days. Src kinase was activated, but not Rock, PKCα, JNK, or P38Mapk. Mitochondrial antioxidant Visomitin (SkQ1, mitochondrial targeted antioxidant) and Src kinase inhibitor eCF506 significantly slowed the increase in CT, with concomitant decreased stromal lactate retention, improved barrier function, reduced Src activation and Cldn1 phosphorylation, and rescued MCT2 and MCT4 expression. Conclusions: Slc4a11 KO-induced CE oxidative stress triggered increased Src kinase activity that resulted in perturbation of the pump components and barrier function of the CE. Full article

(This article belongs to the Special Issue Cell Biology of the Cornea and Ocular Surface)

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37 pages, 9392 KiB

Open AccessArticle

The First Transcriptomic Atlas of the Adult Lacrimal Gland Reveals Epithelial Complexity and Identifies Novel Progenitor Cells in Mice

by Vanessa Delcroix, Olivier Mauduit, Hyun Soo Lee, Anastasiia Ivanova, Takeshi Umazume, Sarah M. Knox, Cintia S. de Paiva, Darlene A. Dartt and Helen P. Makarenkova

Cells 2023, 12(10), 1435; https://doi.org/10.3390/cells12101435 - 21 May 2023

Cited by 4 | Viewed by 2469

Abstract

The lacrimal gland (LG) secretes aqueous tears. Previous studies have provided insights into the cell lineage relationships during tissue morphogenesis. However, little is known about the cell types composing the adult LG and their progenitors. Using scRNAseq, we established the first comprehensive cell atlas of the adult mouse LG to investigate the cell hierarchy, its secretory repertoire, and the sex differences. Our analysis uncovered the complexity of the stromal landscape. Epithelium subclustering revealed myoepithelial cells, acinar subsets, and two novel acinar subpopulations: Tfrc^hi and Car6^hi cells. The ductal compartment contained Wfdc2+ multilayered ducts and an Ltf+ cluster formed by luminal and intercalated duct cells. Kit+ progenitors were identified as: Krt14+ basal ductal cells, Aldh1a1+ cells of Ltf+ ducts, and Sox10+ cells of the Car6^hi acinar and Ltf+ epithelial clusters. Lineage tracing experiments revealed that the Sox10+ adult populations contribute to the myoepithelial, acinar, and ductal lineages. Using scRNAseq data, we found that the postnatally developing LG epithelium harbored key features of putative adult progenitors. Finally, we showed that acinar cells produce most of the sex-biased lipocalins and secretoglobins detected in mouse tears. Our study provides a wealth of new data on LG maintenance and identifies the cellular origin of sex-biased tear components. Full article

(This article belongs to the Special Issue Cell Biology of the Cornea and Ocular Surface)

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21 pages, 3108 KiB

Open AccessReview

Modulating Growth Factor Receptor Signaling to Promote Corneal Epithelial Homeostasis

by Kate E. Tarvestad-Laise and Brian P. Ceresa

Cells 2023, 12(23), 2730; https://doi.org/10.3390/cells12232730 - 29 Nov 2023

Cited by 2 | Viewed by 1138

Abstract

The corneal epithelium is the first anatomical barrier between the environment and the cornea; it is critical for proper light refraction onto the retina and prevents pathogens (e.g., bacteria, viruses) from entering the immune-privileged eye. Trauma to the highly innervated corneal epithelium is extremely painful and if not resolved quickly or properly, can lead to infection and ultimately blindness. The healthy eye produces its own growth factors and is continuously bathed in tear fluid that contains these proteins and other nutrients to maintain the rapid turnover and homeostasis of the ocular surface. In this article, we review the roles of growth factors in corneal epithelial homeostasis and regeneration and some of the limitations to their use therapeutically. Full article

(This article belongs to the Special Issue Cell Biology of the Cornea and Ocular Surface)

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23 pages, 10786 KiB

Open AccessReview

Animal Models for the Study of Keratoconus

by Rachel Hadvina, Amy Estes and Yutao Liu

Cells 2023, 12(23), 2681; https://doi.org/10.3390/cells12232681 - 22 Nov 2023

Cited by 1 | Viewed by 1272

Abstract

Keratoconus (KC) is characterized by localized, central thinning and cone-like protrusion of the cornea. Its precise etiology remains undetermined, although both genetic and environmental factors are known to contribute to disease susceptibility. Due to KC’s complex nature, there is currently no ideal animal model to represent both the corneal phenotype and underlying pathophysiology. Attempts to establish a KC model have involved mice, rats, and rabbits, with some additional novel animals suggested. Genetic animal models have only been attempted in mice. Similarly, spontaneously occurring animal models for KC have only been discovered in mice. Models generated using chemical or environmental treatments have been attempted in mice, rats, and rabbits. Among several methods used to induce KC in animals, ultraviolet radiation exposure and treatment with collagenase are some of the most prevalent. There is a clear need for an experimental model animal to elucidate the underlying mechanisms behind the development and progression of keratoconus. An appropriate animal model could also aid in the development of treatments to slow or arrest the disorder. Full article

(This article belongs to the Special Issue Cell Biology of the Cornea and Ocular Surface)

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