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Molecular and Cellular Mechanisms of Corneal Fibrosis/Scarring and Advances in Therapy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 42919

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Dr. Gary Hin-Fai Yam

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Guest Editor

1. Tissue Engineering and Stem Cell Group, Singapore Eye Research Institute, Singapore 169856, Singapore
2. Eye-Academic Clinical Program, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore 169857, Singapore
Interests: cornea cell biology; cell culture
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Vishal Jhanji

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Co-Guest Editor

Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, USA
Interests: complex ocular surface disorders (graft versus host disease, Stevens Johnson syndrome, cicatricial disorders); keratoconus; other corneal ectasias and collagen crosslinking; corneal infections; corneal transplantation; corneal imaging
Special Issues, Collections and Topics in MDPI journals

Dr. Matthias Fuest

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Co-Guest Editor

Department of Ophthalmology, RWTH Aachen University, 52074 Aachen, Germany
Interests: perforating and lamellar corneal transplantation; ocular surface diseases; cataract; glaucoma; corneal stromal diseases; corneal tissue engineering; corneal wound healing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Corneal blindness is a leading cause of vision loss. The cornea is susceptible to injury by external agents. Typical corneal injuries include trauma, thermal/chemical burns, and infection. The wound healing response results in a deposition of disorganized and fibrotic extracellular matrix (ECM), contributing to corneal scarring that impedes vision. While the only treatment option is the replacement of damaged corneas through transplantation using cadaveric donor corneas, the global shortage of donor tissues and its sustainability amidst a growing aging population is of utmost concern. This Special Issue of IJMS aims to provide an overview of the molecular and cellular mechanisms associated with corneal fibrosis and scarring, as well as the latest research on the treatment modalities of corneal scarring and their short- and long-term consequences. This will be of interest to scientists and clinicians working to fight against corneal blindness. This Special Issue will consider reviews and original research manuscripts with topics including (but not limited to) the underlying mechanisms of stromal wound healing and ECM remodelling, diagnostics/prognostics, as well as new insights on treatment modalities associated with fibrosis and scar management (such as early wound intervention and cell-based and cell-free strategies)

Dr. Gary Hin-Fai Yam
Prof. Dr. Vishal Jhanji
Dr. Matthias Fuest
Guest Editors

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Keywords

corneal injury
corneal diseases
fibrosis
scarring
basic research
clinical research
animal models
pathophysiology
diagnosis
treatment

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

5 pages, 209 KiB

Open AccessEditorial

Molecular and Cellular Mechanisms of Corneal Scarring and Advances in Therapy

by Matthias Fuest, Vishal Jhanji and Gary Hin-Fai Yam

Int. J. Mol. Sci. 2023, 24(9), 7777; https://doi.org/10.3390/ijms24097777 - 24 Apr 2023

Cited by 5 | Viewed by 1568

Abstract

On the basis of WHO global blindness data, it may be stated that 23 million people globally suffer from unilateral corneal blindness, while 4 [...] Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Corneal Fibrosis/Scarring and Advances in Therapy)

Research

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21 pages, 6191 KiB

Open AccessArticle

Mesenchymal Stem Cell Exosomes as Immunomodulatory Therapy for Corneal Scarring

by Hon Shing Ong, Andri K. Riau, Gary Hin-Fai Yam, Nur Zahirah Binte M. Yusoff, Evelina J. Y. Han, Tze-Wei Goh, Ruenn Chai Lai, Sai Kiang Lim and Jodhbir S. Mehta

Int. J. Mol. Sci. 2023, 24(8), 7456; https://doi.org/10.3390/ijms24087456 - 18 Apr 2023

Cited by 13 | Viewed by 3201

Abstract

Corneal scarring is a leading cause of worldwide blindness. Human mesenchymal stem cells (MSC) have been reported to promote corneal wound healing through secreted exosomes. This study investigated the wound healing and immunomodulatory effects of MSC-derived exosomes (MSC-exo) in corneal injury through an established rat model of corneal scarring. After induction of corneal scarring by irregular phototherapeutic keratectomy (irrPTK), MSC exosome preparations (MSC-exo) or PBS vehicle as controls were applied to the injured rat corneas for five days. The animals were assessed for corneal clarity using a validated slit-lamp haze grading score. Stromal haze intensity was quantified using in-vivo confocal microscopy imaging. Corneal vascularization, fibrosis, variations in macrophage phenotypes, and inflammatory cytokines were evaluated using immunohistochemistry techniques and enzyme-linked immunosorbent assays (ELISA) of the excised corneas. Compared to the PBS control group, MSC-exo treatment group had faster epithelial wound closure (0.041), lower corneal haze score (p = 0.002), and reduced haze intensity (p = 0.004) throughout the follow-up period. Attenuation of corneal vascularisation based on CD31 and LYVE-1 staining and reduced fibrosis as measured by fibronectin and collagen 3A1 staining was also observed in the MSC-exo group. MSC-exo treated corneas also displayed a regenerative immune phenotype characterized by a higher infiltration of CD163+, CD206+ M2 macrophages over CD80+, CD86+ M1 macrophages (p = 0.023), reduced levels of pro-inflammatory IL-1β, IL-8, and TNF-α, and increased levels of anti-inflammatory IL-10. In conclusion, topical MSC-exo could alleviate corneal insults by promoting wound closure and reducing scar development, possibly through anti-angiogenesis and immunomodulation towards a regenerative and anti-inflammatory phenotype. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Corneal Fibrosis/Scarring and Advances in Therapy)

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17 pages, 11495 KiB

Open AccessArticle

A Framework for Human Corneal Endothelial Cell Culture and Preliminary Wound Model Experiments with a New Cell Tracking Approach

by Francisco Bandeira, Gustavo Teixeira Grottone, Joyce Luciana Covre, Priscila Cardoso Cristovam, Renata Ruoco Loureiro, Francisco Irochima Pinheiro, Ricardo Pedro Casaroli-Marano, Waleska Donato and José Álvaro Pereira Gomes

Int. J. Mol. Sci. 2023, 24(3), 2982; https://doi.org/10.3390/ijms24032982 - 3 Feb 2023

Cited by 5 | Viewed by 3114

Abstract

Cell injection therapy is emerging as an alternative to treat corneal endothelial dysfunction (CED) and to avoid corneal scarring due to bullous keratopathy. However, establishing a standardized culture procedure that provides appropriate cell yield while retaining functional features remains a challenge. Here, we describe a detailed framework obtained from in vitro culture of human corneal endothelial cells (HCECs) and comparative in vivo experimental models for CED treatment with a new cell tracking approach. Two digestion methods were compared regarding HCEC morphology and adhesion. The effect of Y-27632 (ROCKi) supplementation on final cell yield was also assessed. Cell adhesion efficacy with two cell delivery systems (superparamagnetic embedding and cell suspension) was evaluated in an ex vivo human cornea model and in an in vivo rabbit CED model. The injection of supplemented culture medium or balanced salt solution (BSS) was used for the positive and negative controls, respectively. HCEC isolation with collagenase resulted in better morphology and adhesion of cultured HCEC when compared to EDTA. Y-27632 supplementation resulted in a 2.6-fold increase in final cell yield compared to the control. Ex vivo and in vivo adhesion with both cell delivery systems was confirmed by cell tracker fluorescence detection. Corneal edema and opacity improved in both animal groups treated with cultured HCEC. The corneas in the control groups remained opaque. Both HCEC delivery systems seemed comparable as treatments for CED and for the prevention of corneal scarring. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Corneal Fibrosis/Scarring and Advances in Therapy)

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22 pages, 3083 KiB

Open AccessArticle

Cytoprotective Effects of Human Platelet Lysate during the Xeno-Free Culture of Human Donor Corneas

by Delia Talpan, Sabine Salla, Linus Meusel, Peter Walter, Chao-Chung Kuo, Julia Franzen and Matthias Fuest

Int. J. Mol. Sci. 2023, 24(3), 2882; https://doi.org/10.3390/ijms24032882 - 2 Feb 2023

Cited by 2 | Viewed by 2253

Abstract

We evaluated the suitability of 2% human platelet lysate medium (2%HPL) as a replacement for 2% fetal bovine serum medium (2%FBS) for the xeno-free organ culture of human donor corneas. A total of 32 corneas from 16 human donors were cultured in 2%FBS for 3 days (TP1), then evaluated using phase contrast microscopy (endothelial cell density (ECD) and cell morphology). Following an additional 25-day culture period (TP2) in either 2%FBS or 2%HPL, the pairs were again compared using microscopy; then stroma and Descemet membrane/endothelium (DmE) were processed for next generation sequencing (NGS). At TP2 the ECD was higher in the 2%HPL group (2179 ± 288 cells/mm²) compared to 2%FBS (2113 ± 331 cells/mm²; p = 0.03), and endothelial cell loss was lower (ECL HPL = −0.7% vs. FBS = −3.8%; p = 0.01). There were no significant differences in cell morphology between TP1 and 2, or between 2%HPL and 2%FBS. NGS showed the differential expression of 1644 genes in endothelial cells and 217 genes in stromal cells. It was found that 2%HPL led to the upregulation of cytoprotective, anti-inflammatory and anti-fibrotic genes (HMOX1, SERPINE1, ANGPTL4, LEFTY2, GADD45B, PLIN2, PTX3, GFRA1/2), and the downregulation of pro-inflammatory/apoptotic genes (e.g., CXCL14, SIK1B, PLK5, PPP2R3B, FABP5, MAL, GATA3). 2%HPL is a suitable xeno-free substitution for 2%FBS in human cornea organ culture, inducing less ECL and producing potentially beneficial alterations in gene expression. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Corneal Fibrosis/Scarring and Advances in Therapy)

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16 pages, 4980 KiB

Open AccessArticle

Epigenetic Regulation of Corneal Epithelial Differentiation by TET2

by Yuzuru Sasamoto, Siyuan Wu, Catherine A. A. Lee, Jason Y. Jiang, Bruce R. Ksander, Markus H. Frank and Natasha Y. Frank

Int. J. Mol. Sci. 2023, 24(3), 2841; https://doi.org/10.3390/ijms24032841 - 2 Feb 2023

Cited by 3 | Viewed by 2413

Abstract

Epigenetic DNA modification by 5-hydroxymethylcytosine (5hmC), generated by the Ten-eleven translocation (TET) dioxygenases, regulates diverse biological functions in many organ tissues, including the mammalian eye. For example, 5hmC has been shown to be involved in epigenetic regulation of retinal gene expression. However, a functional role of 5hmC in corneal differentiation has not been investigated to date. Here, we examined 5hmC and TET function in the human cornea. We found 5hmC highly expressed in MUC16-positive terminally differentiated cells that also co-expressed the 5hmC-generating enzyme TET2. TET2 knockdown (KD) in cultured corneal epithelial cells led to significant reductions of 5hmC peak distributions and resulted in transcriptional repression of molecular pathways involved in corneal differentiation, as evidenced by downregulation of MUC4, MUC16, and Keratin 12. Additionally, integrated TET2 KD RNA-seq and genome-wide Reduced Representation Hydroxymethylation Profiling revealed novel epigenetically regulated genes expressed by terminally differentiated cells, including KRT78, MYEOV, and MAL. In aggregate, our findings reveal a novel function of TET2 in the epigenetic regulation of corneal epithelial gene expression and identify novel TET2-controlled genes expressed in differentiated corneal epithelial cells. These results point to potential roles for TET2 induction strategies to enhance treatment of corneal diseases associated with abnormal epithelial maturation. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Corneal Fibrosis/Scarring and Advances in Therapy)

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15 pages, 1877 KiB

Open AccessArticle

Antifibrotic Effects of Caffeine, Curcumin and Pirfenidone in Primary Human Keratocytes

by Delia Talpan, Sabine Salla, Nina Seidelmann, Peter Walter and Matthias Fuest

Int. J. Mol. Sci. 2023, 24(2), 1461; https://doi.org/10.3390/ijms24021461 - 11 Jan 2023

Cited by 8 | Viewed by 11789

Abstract

We evaluated the small molecules (AFM) caffeine, curcumin and pirfenidone to find non-toxic concentrations reducing the transformation of activated human corneal stromal keratocytes (aCSK) to scar-inducing myofibroblasts (MYO-SF). CSK were isolated from 16 human corneas unsuitable for transplantation and expanded for three passages in control medium (0.5% FBS). Then, aCSK were exposed to concentrations of caffeine of 0–500 μM, curcumin of 0–200 μM, pirfenidone of 0–2.2 nM and the profibrotic cytokine TGF-β1 (10 ng/mL) for 48 h. Alterations in viability and gene expression were evaluated by cell viability staining (FDA/PI), real-time polymerase chain reaction (RT-PCR) and immunocytochemistry. We found that all AFMs reduced cell counts at high concentrations. The highest concentrations with no toxic effect were 100 µM of caffeine, 20 µM of curcumin and 1.1 nM of pirfenidone. The addition of TGF-β1 to the control medium effectively transformed aCSK into myofibroblasts (MYO-SF), indicated by a 10-fold increase in α-smooth muscle actin (SMA) expression, a 39% decrease in lumican (LUM) expression and a 98% decrease in ALDH3A1 expression (p < 0.001). The concentrations of 100 µM of caffeine, 20/50 µM of curcumin and 1.1 nM of pirfenidone each significantly reduced SMA expression under TGF-β1 stimulation (p ≤ 0.024). LUM and ALDH3A1 expression remained low under TGF-β1 stimulation, independently of AFM supplementation. Immunocytochemistry showed that 100 µM of caffeine, 20 µM of curcumin and 1.1 nM of pirfenidone reduce the conversion rate of aCSK to SMA⁺ MYO-SF. In conclusion, in aCSK, 100 µM of caffeine, 20 µM of curcumin and 1.1 nM of pirfenidone significantly reduced SMA expression and MYO-SF conversion under TGF-β1 stimulation, with no influence on cell counts. However, the AFMs were unable to protect aCSK from characteristic marker loss. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Corneal Fibrosis/Scarring and Advances in Therapy)

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16 pages, 5342 KiB

Open AccessArticle

Disulfiram Ophthalmic Solution Inhibited Macrophage Infiltration by Suppressing Macrophage Pseudopodia Formation in a Rat Corneal Alkali Burn Model

by Toyo Ikebukuro, Takeshi Arima, Momoko Kasamatsu, Yuji Nakano, Yutaro Tobita, Masaaki Uchiyama, Yuya Terashima, Etsuko Toda, Akira Shimizu and Hiroshi Takahashi

Int. J. Mol. Sci. 2023, 24(1), 735; https://doi.org/10.3390/ijms24010735 - 1 Jan 2023

Cited by 7 | Viewed by 3019

Abstract

FROUNT is an intracellular protein that promotes pseudopodia formation by binding to the chemokine receptors CCR2 and CCR5 on macrophages. Recently, disulfiram (DSF), a drug treatment for alcoholism, was found to have FROUNT inhibitory activity. In this study, we investigated the effect of DSF eye drops in a rat corneal alkali burn model. After alkali burn, 0.5% DSF eye drops (DSF group) and vehicle eye drops (Vehicle group) were administered twice daily. Immunohistochemical observations and real-time reverse transcription-polymerase chain reaction (RT-PCR) analyses were performed at 6 h and 1, 4, and 7 days after alkali burn. Results showed a significant decrease in macrophage accumulation in the cornea in the DSF group, but no difference in neutrophils. RT-PCR showed decreased expression of macrophage-associated cytokines in the DSF group. Corneal scarring and neovascularization were also suppressed in the DSF group. Low-vacuum scanning electron microscopy imaging showed that macrophage length was significantly shorter in the DSF group, reflecting the reduced extension of pseudopodia. These results suggest that DSF inhibited macrophage infiltration by suppressing macrophage pseudopodia formation. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Corneal Fibrosis/Scarring and Advances in Therapy)

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24 pages, 3573 KiB

Open AccessArticle

Transcriptomic Profiling of Human Limbus-Derived Stromal/Mesenchymal Stem Cells—Novel Mechanistic Insights into the Pathways Involved in Corneal Wound Healing

by Fatemeh Tavakkoli, Mukesh Damala, Madhuri Amulya Koduri, Abhilash Gangadharan, Amit K. Rai, Debasis Dash, Sayan Basu and Vivek Singh

Int. J. Mol. Sci. 2022, 23(15), 8226; https://doi.org/10.3390/ijms23158226 - 26 Jul 2022

Cited by 6 | Viewed by 2778

Abstract

Limbus-derived stromal/mesenchymal stem cells (LMSCs) are vital for corneal homeostasis and wound healing. However, despite multiple pre-clinical and clinical studies reporting the potency of LMSCs in avoiding inflammation and scarring during corneal wound healing, the molecular basis for the ability of LMSCs remains unknown. This study aimed to uncover the factors and pathways involved in LMSC-mediated corneal wound healing by employing RNA-Sequencing (RNA-Seq) in human LMSCs for the first time. We characterized the cultured LMSCs at the stages of initiation (LMSC−P0) and pure population (LMSC−P3) and subjected them to RNA-Seq to identify the differentially expressed genes (DEGs) in comparison to native limbus and cornea, and scleral tissues. Of the 28,000 genes detected, 7800 DEGs were subjected to pathway-specific enrichment Gene Ontology (GO) analysis. These DEGs were involved in Wnt, TGF-β signaling pathways, and 16 other biological processes, including apoptosis, cell motility, tissue remodeling, and stem cell maintenance, etc. Two hundred fifty-four genes were related to wound healing pathways. COL5A1 (11.81 ± 0.48) and TIMP1 (20.44 ± 0.94) genes were exclusively up-regulated in LMSC−P3. Our findings provide new insights involved in LMSC-mediated corneal wound healing. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Corneal Fibrosis/Scarring and Advances in Therapy)

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19 pages, 4521 KiB

Open AccessArticle

Combined Therapy Using Human Corneal Stromal Stem Cells and Quiescent Keratocytes to Prevent Corneal Scarring after Injury

by Vishal Jhanji, Mithun Santra, Andri K. Riau, Moira L. Geary, Tianbing Yang, Elizabeth Rubin, Nur Zahirah Binte M. Yusoff, Deepinder K. Dhaliwal, Jodhbir S. Mehta and Gary Hin-Fai Yam

Int. J. Mol. Sci. 2022, 23(13), 6980; https://doi.org/10.3390/ijms23136980 - 23 Jun 2022

Cited by 19 | Viewed by 3035

Abstract

Corneal blindness due to scarring is conventionally treated by corneal transplantation, but the shortage of donor materials has been a major issue affecting the global success of treatment. Pre-clinical and clinical studies have shown that cell-based therapies using either corneal stromal stem cells (CSSC) or corneal stromal keratocytes (CSK) suppress corneal scarring at lower levels. Further treatments or strategies are required to improve the treatment efficacy. This study examined a combined cell-based treatment using CSSC and CSK in a mouse model of anterior stromal injury. We hypothesize that the immuno-regulatory nature of CSSC is effective to control tissue inflammation and delay the onset of fibrosis, and a subsequent intrastromal CSK treatment deposited collagens and stromal specific proteoglycans to recover a native stromal matrix. Using optimized cell doses, our results showed that the effect of CSSC treatment for suppressing corneal opacities was augmented by an additional intrastromal CSK injection, resulting in better corneal clarity. These in vivo effects were substantiated by a further downregulated expression of stromal fibrosis genes and the restoration of stromal fibrillar organization and regularity. Hence, a combined treatment of CSSC and CSK could achieve a higher clinical efficacy and restore corneal transparency, when compared to a single CSSC treatment. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Corneal Fibrosis/Scarring and Advances in Therapy)

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Review

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24 pages, 2044 KiB

Open AccessReview

Human SMILE-Derived Stromal Lenticule Scaffold for Regenerative Therapy: Review and Perspectives

by Mithun Santra, Yu-Chi Liu, Vishal Jhanji and Gary Hin-Fai Yam

Int. J. Mol. Sci. 2022, 23(14), 7967; https://doi.org/10.3390/ijms23147967 - 19 Jul 2022

Cited by 17 | Viewed by 3665

Abstract

A transparent cornea is paramount for vision. Corneal opacity is one of the leading causes of blindness. Although conventional corneal transplantation has been successful in recovering patients’ vision, the outcomes are challenged by a global lack of donor tissue availability. Bioengineered corneal tissues are gaining momentum as a new source for corneal wound healing and scar management. Extracellular matrix (ECM)-scaffold-based engineering offers a new perspective on corneal regenerative medicine. Ultrathin stromal laminar tissues obtained from lenticule-based refractive correction procedures, such as SMall Incision Lenticule Extraction (SMILE), are an accessible and novel source of collagen-rich ECM scaffolds with high mechanical strength, biocompatibility, and transparency. After customization (including decellularization), these lenticules can serve as an acellular scaffold niche to repopulate cells, including stromal keratocytes and stem cells, with functional phenotypes. The intrastromal transplantation of these cell/tissue composites can regenerate native-like corneal stromal tissue and restore corneal transparency. This review highlights the current status of ECM-scaffold-based engineering with cells, along with the development of drug and growth factor delivery systems, and elucidates the potential uses of stromal lenticule scaffolds in regenerative therapeutics. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Corneal Fibrosis/Scarring and Advances in Therapy)

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23 pages, 1858 KiB

Open AccessReview

Extracellular Vesicles in Corneal Fibrosis/Scarring

by Vincent Yeung, Nikolay Boychev, Wissam Farhat, Dimitrios P. Ntentakis, Audrey E. K. Hutcheon, Amy E. Ross and Joseph B. Ciolino

Int. J. Mol. Sci. 2022, 23(11), 5921; https://doi.org/10.3390/ijms23115921 - 25 May 2022

Cited by 20 | Viewed by 4900

Abstract

Communication between cells and the microenvironment is a complex, yet crucial, element in the development and progression of varied physiological and pathological processes. Accumulating evidence in different disease models highlights roles of extracellular vesicles (EVs), either in modulating cell signaling paracrine mechanism(s) or harnessing their therapeutic moiety. Of interest, the human cornea functions as a refractive and transparent barrier that protects the intraocular elements from the external environment. Corneal trauma at the ocular surface may lead to diminished corneal clarity and detrimental effects on visual acuity. The aberrant activation of corneal stromal cells, which leads to myofibroblast differentiation and a disorganized extracellular matrix is a central biological process that may result in corneal fibrosis/scarring. In recent years, understanding the pathological and therapeutic EV mechanism(s) of action in the context of corneal biology has been a topic of increasing interest. In this review, we describe the clinical relevance of corneal fibrosis/scarring and how corneal stromal cells contribute to wound repair and their generation of the stromal haze. Furthermore, we will delve into EV characterization, their subtypes, and the pathological and therapeutic roles they play in corneal scarring/fibrosis. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Corneal Fibrosis/Scarring and Advances in Therapy)

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