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Ye S, Lin J, Zhang Y, Li J, Wang Y, Liang F, Wu J, Xu Y, Lin L, Zhao Y. RhFGF21 protects the skin from UVB irradiation in diabetic mice through the inhibition of epidermal cell apoptosis and macrophage-mediated inflammation via the SIRT1 signaling pathway. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167724. [PMID: 40020529 DOI: 10.1016/j.bbadis.2025.167724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 01/25/2025] [Accepted: 02/13/2025] [Indexed: 03/03/2025]
Abstract
BACKGROUND Ultraviolet B (UVB) irradiation can damage skin tissue. Diabetes aggravates skin lesions. Fibroblast growth factor 21 (FGF21) is significantly involved in exerting protective effects and facilitating tissue repair. Therefore, this study aimed to investigate the impact of recombinant human FGF21 (rhFGF21) on diabetic skin affected by UVB damage. METHODS UVB irradiation (270 mJ/cm2) was administered to diabetic mice for 5 consecutive days to establish UVB-irradiated skin injury, and rhFGF21 was administered daily after irradiation. Human immortalized keratinocytes (HaCaT) and mouse peritoneal macrophages (MPMs) were cultured under high glucose (HG) conditions for 3 days, followed by treatment with rhFGF21 for 1 h before UVB irradiation or lipopolysaccharide (LPS) stimulation. We analyzed the effects of UVB irradiation on diabetic skin via laser Doppler flowmetry, histopathological staining, TUNEL assays, RT-PCR, Western blotting, MTT assays and Hoechst 33258 staining. RESULTS Our findings indicated that the skin of diabetic mice was more severely damaged by UVB irradiation, and rhFGF21 alleviated this damage. RhFGF21 inhibited apoptosis and inflammatory responses in the skin tissues of diabetic mice. These changes were primarily reflected in increase of the sirtuin 1 (SIRT1) level in epidermal cells and peritoneal macrophages of mice. Moreover, rhFGF21 not only increased the survival rate of HaCaT cells but also decreased the generation of pro-inflammatory cytokines in MPMs. Notably, SIRT1 inhibitor (EX527) was capable of reversing these effects. CONCLUSIONS RhFGF21 attenuates UVB-induced damage to the skin of diabetic mice, predominantly by suppressing epidermal cell apoptosis and macrophage-mediated inflammatory responses via the SIRT signaling pathway.
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Affiliation(s)
- Shasha Ye
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jingjing Lin
- Pharmacy department, Wenzhou TCM Hospital of Zhejiang Chinese Medical University, Wenzhou, Zhejiang, China
| | - Yujie Zhang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jiana Li
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yichen Wang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Fei Liang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Junyi Wu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yifan Xu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Li Lin
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China; State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Yeli Zhao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
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Dai J, Rayana NP, Peng M, Sugali CK, Harvey DH, Dhamodaran K, Yu E, Dalloul JM, Liu S, Mao W. Inhibition of pterygium cell fibrosis by the Rho kinase inhibitor. Sci Rep 2024; 14:30930. [PMID: 39730553 DOI: 10.1038/s41598-024-81659-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Accepted: 11/28/2024] [Indexed: 12/29/2024] Open
Abstract
Pterygium is an ocular disease in which the conjunctival tissue invades the cornea. When the pterygium tissue reaches the pupillary region, the visual function of the patient is affected. Currently, surgical removal is the only effective treatment. However, the recurrence rate of pterygium after surgery can be high. Pterygium is also a health disparity issue since it is more prevalent in the Hispanic and Latino American population. In this study, we determined if the Rho kinase inhibitor can be used to prevent pterygium recurrence since its anti-fibrosis effects have been reported in other cell and tissue types. We cultured primary pterygium cells from pterygium tissues from Hispanic and Latino American, African American, Caucasian, and Asian donors, and used those cells for viability assays, scratch assays, migration assays, and immunostaining of F-actin, fibronectin, collagen I and α smooth muscle actin. We found that the Rho kinase inhibitor Y27632 decreased cell viability, wound healing, cell migration, as well as the expression of extracellular matrix and myofibroblast markers in cultured pterygium cells. We believe that Rho kinase inhibitors are a potential post-surgical treatment to prevent pterygium recurrence.
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Affiliation(s)
- Jiannong Dai
- Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, RM305v, 1160 W. Michigan St., Indianapolis, IN, 46202, USA
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, USA
| | - Naga Pradeep Rayana
- Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, RM305v, 1160 W. Michigan St., Indianapolis, IN, 46202, USA
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, USA
| | - Michael Peng
- Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, RM305v, 1160 W. Michigan St., Indianapolis, IN, 46202, USA
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, USA
| | - Chenna Kesavulu Sugali
- Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, RM305v, 1160 W. Michigan St., Indianapolis, IN, 46202, USA
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, USA
| | - Devon H Harvey
- Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, RM305v, 1160 W. Michigan St., Indianapolis, IN, 46202, USA
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, USA
| | - Kamesh Dhamodaran
- Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, RM305v, 1160 W. Michigan St., Indianapolis, IN, 46202, USA
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, USA
| | - Eric Yu
- Fulton Science Academy Private School, Alpharetta, GA, USA
| | - Joseph M Dalloul
- Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, RM305v, 1160 W. Michigan St., Indianapolis, IN, 46202, USA
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, USA
| | - Shaohui Liu
- Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, RM305v, 1160 W. Michigan St., Indianapolis, IN, 46202, USA
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, USA
| | - Weiming Mao
- Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, RM305v, 1160 W. Michigan St., Indianapolis, IN, 46202, USA.
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, USA.
- Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, USA.
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, USA.
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, USA.
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Lee SJ, Koh A, Lee SH, Kim KW. Distinct activation of M1 and M2 macrophages in the primary pterygium lymphangiogenesis. Exp Eye Res 2024; 248:110108. [PMID: 39326777 DOI: 10.1016/j.exer.2024.110108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/06/2024] [Accepted: 09/23/2024] [Indexed: 09/28/2024]
Abstract
The precise role and innate immunological mechanisms underlying lymphangiogenesis in pterygium remain unclear. This study aimed to investigate the presence of M1 and M2 macrophages and their correlation with pro-lymphangiogenic activation and lymphatic endothelial expression in human pterygium stromal tissues. We analyzed human pterygium and subject-matched normal conjunctival tissues for the expression of these factors and conducted in vitro experiments to assess interactions between macrophages and pterygium fibroblasts. Myeloid and M1 macrophage markers were upregulated in pterygium. M1 macrophages were associated with the upregulation of pro-lymphangiogenic vascular endothelial growth factor C (Vegfc) in pterygium tissues and induced inflammatory signals in pterygium fibroblasts. In contrast, lymphatic vessel endothelial hyaluronan receptor 1 (Lyve1) expression was associated with M2 markers but not with M1 markers. Notably, the clinical severity of pterygium was inversely correlated with the expression of the M2 marker Cd163. These findings suggest that M1 and M2 macrophages play distinct roles in the pathogenesis of pterygium, with M1 macrophages enhancing lymphangiogenic stimulation and inflammatory responses, while M2 macrophages are associated with Lyve1 expression and reduced severity of pterygium. Understanding these mechanisms may advance our current understanding of lymphatic biology in pterygium.
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Affiliation(s)
- Soo Jin Lee
- Chung-Ang Ocular Surface Restoration via Immune-inflammation Alleviation (CORIA) Laboratory, Seoul, Republic of Korea
| | - Ahra Koh
- Chung-Ang Ocular Surface Restoration via Immune-inflammation Alleviation (CORIA) Laboratory, Seoul, Republic of Korea; Chung-Ang University Graduate School, Seoul, Republic of Korea
| | - Seung Hyeun Lee
- Chung-Ang Ocular Surface Restoration via Immune-inflammation Alleviation (CORIA) Laboratory, Seoul, Republic of Korea; Chung-Ang University Graduate School, Seoul, Republic of Korea; Department of Ophthalmology, Chung-Ang University Gwangmyeong Hospital, Gwangmyeong-si, Gyeonggi-do, Republic of Korea
| | - Kyoung Woo Kim
- Chung-Ang Ocular Surface Restoration via Immune-inflammation Alleviation (CORIA) Laboratory, Seoul, Republic of Korea; Department of Ophthalmology, Chung-Ang University College of Medicine, Chung-Ang University Hospital, Seoul, Republic of Korea.
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Lee SJ, Koh A, Lee SH, Kim KW. Efficacy of epidermal growth factor in suppressing inflammation and proliferation in pterygial fibroblasts through interactions with microenvironmental M1 macrophages. Sci Rep 2024; 14:22601. [PMID: 39349715 PMCID: PMC11442942 DOI: 10.1038/s41598-024-74413-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 09/25/2024] [Indexed: 10/04/2024] Open
Abstract
The protein epidermal growth factor (EGF), which plays a crucial role in promoting cell proliferation and survival, has recently demonstrated potential in reducing inflammation. In this study, we examined the impact of EGF on the anti-inflammatory and anti-proliferative properties of pterygium, a prevalent hypervascular proliferative disease affecting the ocular surface. In surgically excised tissues, markers for fibrotic and inflammatory signals, including VIM, ACTA2, FAP, MMP2, VCAM1, ICAM1, CD86, IL6, and IL1B were upregulated in the pterygium body stroma compared to the normal conjunctival stroma. EGF exerted anti-inflammatory and anti-vasculogenic effects on pterygial fibroblasts when co-cultured with M1 macrophages. Moreover, exosomes derived from EGF-preconditioned M1 macrophages suppressed the heightened inflammatory and vasculogenic signals in pterygial fibroblasts induced by exosomes from M1 macrophages. Paradoxically, the proliferation of pterygial fibroblasts was inhibited by EGF in the in vitro microenvironment with M1 macrophages, despite EGF being known as a growth factor. EGF-preconditioning of M1 macrophages rescued the increased proliferation of pterygial fibroblasts induced by exosomes from M1 macrophages. In conclusion, our findings demonstrate that EGF effectively mitigates inflammation and proliferation in pterygial fibroblasts within a microenvironment containing M1 macrophages.
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Affiliation(s)
- Soo Jin Lee
- Chung-Ang Ocular Surface Restoration via Immune-inflammation Alleviation (CORIA) Laboratory, Seoul, Republic of Korea
| | - Ahra Koh
- Chung-Ang Ocular Surface Restoration via Immune-inflammation Alleviation (CORIA) Laboratory, Seoul, Republic of Korea
- Chung-Ang University Graduate School, Seoul, Republic of Korea
| | - Seung Hyeun Lee
- Chung-Ang Ocular Surface Restoration via Immune-inflammation Alleviation (CORIA) Laboratory, Seoul, Republic of Korea
- Department of Ophthalmology, Chung-Ang University Gwangmyeong Hospital, Gwangmyeong-si, Gyeonggi-do, Republic of Korea
| | - Kyoung Woo Kim
- Chung-Ang Ocular Surface Restoration via Immune-inflammation Alleviation (CORIA) Laboratory, Seoul, Republic of Korea.
- Chung-Ang University Graduate School, Seoul, Republic of Korea.
- Department of Ophthalmology, Chung-Ang University College of Medicine, Chung-Ang University Hospital, 102 Heukseok-ro, Dongjak-gu, Seoul, 06973, Republic of Korea.
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Fang X, Zhang S, Wu M, Luo Y, Chen X, Zhou Y, Zhang Y, Liu X, Yao X. Systemic comparison of molecular characteristics in different skin fibroblast senescent models. Chin Med J (Engl) 2024:00029330-990000000-01259. [PMID: 39329281 DOI: 10.1097/cm9.0000000000003312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Indexed: 09/28/2024] Open
Abstract
BACKGROUND Senescent human skin primary fibroblast (FB) models have been established for studying aging-related, proliferative, and inflammatory skin diseases. The aim of this study was to compare the transcriptome characteristics of human primary dermal FBs from children and the elderly with four senescence models. METHODS Human skin primary FBs were obtained from healthy children (FB-C) and elderly donors (FB-E). Senescence models were generated by ultraviolet B irradiation (FB-UVB), D-galactose stimulation (FB-D-gal), atazanavir treatment (FB-ATV), and replication exhaustion induction (FB-P30). Flow cytometry, immunofluorescence staining, real-time quantitative polymerase chain reaction, co-culturing with immune cells, and bulk RNA sequencing were used for systematic comparisons of the models. RESULTS In comparison with FB-C, FB-E showed elevated expression of senescence-related genes related to the skin barrier and extracellular matrix, proinflammatory factors, chemokines, oxidative stress, and complement factors. In comparison with FB-E, FB-UVB and FB-ATV showed higher levels of senescence and expression of the genes related to the senescence-associated secretory phenotype (SASP), and their shaped immune microenvironment highly facilitated the activation of downstream immune cells, including T cells, macrophages, and natural killer cells. FB-P30 was most similar to FB-E in terms of general transcriptome features, such as FB migration and proliferation, and aging-related characteristics. FB-D-gal showed the lowest expression levels of senescence-related genes. In comparisons with the single-cell RNA sequencing results, FB-E showed almost complete simulation of the transcriptional spectrum of FBs in elderly patients with atopic dermatitis, followed by FB-P30 and FB-UVB. FB-E and FB-P30 showed higher similarity with the FBs in keloids. CONCLUSIONS Each senescent FB model exhibited different characteristics. In addition to showing upregulated expression of natural senescence features, FB-UVB and FB-ATV showed high expression levels of senescence-related genes, including those involved in the SASP, and FB-P30 showed the greatest similarity with FB-E. However, D-galactose-stimulated FBs did not clearly present aging characteristics.
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Affiliation(s)
- Xiaokai Fang
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu 210042, China
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Long Q, Huang C, Zhang L, Jiang H, Zhao S, Zhang L, Zheng X, Ou S, Gu H. A novel tissue-engineered corneal epithelium based on ultra-thin amniotic membrane and mesenchymal stem cells. Sci Rep 2024; 14:17407. [PMID: 39075142 PMCID: PMC11286932 DOI: 10.1038/s41598-024-68219-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 07/22/2024] [Indexed: 07/31/2024] Open
Abstract
Currently, in vitro cultured corneal epithelial transplantation is effective in treating limbal stem cell dysfunction (LSCD). Selecting carriers is crucial for constructing the corneal epithelium through tissue engineering. In this study, the traditional amniotic membrane (AM) was modified, and mesenchymal stem cells (MSCs) were inoculated into the ultra-thin amniotic membrane (UAM) stroma to construct a novel UAM-MSC tissue-engineered corneal epithelial carrier, that could effectively simulate the limbal stem cells (LSCs) microenvironment. The structure of different carriers cultured tissue-engineered corneal epithelium and the managed rabbit LSCD model corneas were observed through hematoxylin-eosin staining. Cell phenotypes were evaluated through fluorescence staining, Western blotting, and RT-qPCR. Additionally, cell junction genes and expression markers related to anti-neovascularization were evaluated using RT-qPCR. Corneal epithelium cell junctions were observed via an electron microscope. The tissue-engineered corneal epithelium culture medium was analyzed through mass spectrometry. Tissue-engineered corneal epithelial cells expanded by LSCs on UAM-MSCs had good transparency. Simultaneously, progenitor cell (K14, PNCA, p63) and corneal epithelial (PAX6) gene expression in tissue-engineered corneal epithelium constructed using UAM-MSCs was higher than that in corneal epithelial cells amplified by UAM and de-epithelialized amniotic membrane. Electron microscopy revealed that corneal epithelial cells grafted with UAM-MSCs were closely connected. In conclusion, the UAM-MSCs vector we constructed could better simulate the limbal microenvironment; the cultured tissue-engineered corneal epithelium had better transparency, anti-neovascularization properties, closer intercellular connections, and closer resemblance to the natural corneal epithelial tissue phenotype.
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Affiliation(s)
- Qiurong Long
- Guizhou Medical University, Guiyang, Guizhou, China
- The Affiliated Hospital of Guizhou Medical University, No.9 Beijing Road, Yunyan District, Guiyang, Guizhou, China
| | - Chao Huang
- Guizhou Medical University, Guiyang, Guizhou, China
| | - Liying Zhang
- Guizhou Medical University, Guiyang, Guizhou, China
- The Affiliated Hospital of Guizhou Medical University, No.9 Beijing Road, Yunyan District, Guiyang, Guizhou, China
| | - Hao Jiang
- Guizhou Medical University, Guiyang, Guizhou, China
- The Affiliated Hospital of Guizhou Medical University, No.9 Beijing Road, Yunyan District, Guiyang, Guizhou, China
| | - Su Zhao
- Guizhou Medical University, Guiyang, Guizhou, China
- The Affiliated Hospital of Guizhou Medical University, No.9 Beijing Road, Yunyan District, Guiyang, Guizhou, China
| | - Lingli Zhang
- Guizhou Medical University, Guiyang, Guizhou, China
| | - Xueer Zheng
- Guizhou Medical University, Guiyang, Guizhou, China
| | - Shangkun Ou
- Guizhou Medical University, Guiyang, Guizhou, China.
- The Affiliated Hospital of Guizhou Medical University, No.9 Beijing Road, Yunyan District, Guiyang, Guizhou, China.
| | - Hao Gu
- Guizhou Medical University, Guiyang, Guizhou, China.
- The Affiliated Hospital of Guizhou Medical University, No.9 Beijing Road, Yunyan District, Guiyang, Guizhou, China.
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Hopkinson A, Notara M, Cursiefen C, Sidney LE. Increased Anti-Inflammatory Therapeutic Potential and Progenitor Marker Expression of Corneal Mesenchymal Stem Cells Cultured in an Optimized Propagation Medium. Cell Transplant 2024; 33:9636897241241992. [PMID: 38602231 PMCID: PMC11010753 DOI: 10.1177/09636897241241992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 02/19/2024] [Accepted: 03/05/2024] [Indexed: 04/12/2024] Open
Abstract
There is a huge unmet need for new treatment modalities for ocular surface inflammatory disorders (OSIDs) such as dry eye disease and meibomian gland dysfunction. Mesenchymal stem cell therapies may hold the answer due to their potent immunomodulatory properties, low immunogenicity, and ability to modulate both the innate and adaptive immune response. MSC-like cells that can be isolated from the corneal stroma (C-MSCs) offer a potential new treatment strategy; however, an optimized culture medium needs to be developed to produce the ideal phenotype for use in a cell therapy to treat OSIDs. The effects of in vitro expansion of human C-MSC in a medium of M199 containing fetal bovine serum (FBS) was compared to a stem cell medium (SCM) containing knockout serum replacement (KSR) with basic fibroblast growth factor (bFGF) and human leukemia inhibitory factor (LIF), investigating viability, protein, and gene expression. Isolating populations expressing CD34 or using siRNA knockdown of CD34 were investigated. Finally, the potential of C-MSC as a cell therapy was assessed using co-culture with an in vitro corneal epithelial cell injury model and the angiogenic effects of C-MSC conditioned medium were evaluated with blood and lymph endothelial cells. Both media supported proliferation of C-MSC, with SCM increasing expression of CD34, ABCG2, PAX6, NANOG, REX1, SOX2, and THY1, supported by increased associated protein expression. Isolating cell populations expressing CD34 protein made little difference to gene expression, however, knockdown of the CD34 gene led to decreased expression of progenitor genes. C-MSC increased viability of injured corneal epithelial cells whilst decreasing levels of cytotoxicity and interleukins-6 and -8. No pro-angiogenic effect of C-MSC was seen. Culture medium can significantly influence C-MSC phenotype and culture in SCM produced a cell phenotype more suitable for further consideration as an anti-inflammatory cell therapy. C-MSC show considerable potential for development as therapies for OSIDs, acting through anti-inflammatory action.
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Affiliation(s)
- Andrew Hopkinson
- Academic Ophthalmology, Mental Health and Clinical Neurosciences, University of Nottingham, Nottingham, UK
| | - Maria Notara
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Koln, Germany
| | - Claus Cursiefen
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Koln, Germany
| | - Laura E. Sidney
- Academic Ophthalmology, Mental Health and Clinical Neurosciences, University of Nottingham, Nottingham, UK
- Regenerating and Modelling Tissues, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK
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Nureen L, Di Girolamo N. Limbal Epithelial Stem Cells in the Diabetic Cornea. Cells 2023; 12:2458. [PMID: 37887302 PMCID: PMC10605319 DOI: 10.3390/cells12202458] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/10/2023] [Accepted: 10/11/2023] [Indexed: 10/28/2023] Open
Abstract
Continuous replenishment of the corneal epithelium is pivotal for maintaining optical transparency and achieving optimal visual perception. This dynamic process is driven by limbal epithelial stem cells (LESCs) located at the junction between the cornea and conjunctiva, which is otherwise known as the limbus. In patients afflicted with diabetes, hyperglycemia-induced impairments in corneal epithelial regeneration results in persistent epithelial and other defects on the ocular surface, termed diabetic keratopathy (DK), which progressively diminish vision and quality of life. Reports of delayed corneal wound healing and the reduced expression of putative stem cell markers in diabetic relative to healthy eyes suggest that the pathogenesis of DK may be associated with the abnormal activity of LESCs. However, the precise role of these cells in diabetic corneal disease is poorly understood and yet to be comprehensively explored. Herein, we review existing literature highlighting aberrant LESC activity in diabetes, focusing on factors that influence their form and function, and emerging therapies to correct these defects. The consequences of malfunctioning or depleted LESC stocks in DK and limbal stem cell deficiency (LSCD) are also discussed. These insights could be exploited to identify novel targets for improving the management of ocular surface complications that manifest in patients with diabetes.
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Affiliation(s)
| | - Nick Di Girolamo
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia;
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Hao S, Chen Z, Gu Y, Chen L, Sheng F, Xu Y, Wu D, Han Y, Lu B, Chen S, Zhao W, Yin H, Wang X, Riazuddin SA, Lou X, Fu Q, Yao K. Long-term PM2.5 exposure disrupts corneal epithelial homeostasis by impairing limbal stem/progenitor cells in humans and rat models. Part Fibre Toxicol 2023; 20:36. [PMID: 37759270 PMCID: PMC10523760 DOI: 10.1186/s12989-023-00540-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 07/13/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND Limbal stem/progenitor cells (LSPCs) play a crucial role in maintaining corneal health by regulating epithelial homeostasis. Although PM2.5 is associated with the occurrence of several corneal diseases, its effects on LSPCs are not clearly understood. METHODS In this study, we explored the correlation between PM2.5 exposure and human limbal epithelial thickness measured by Fourier-domain Optical Coherence Tomography in the ophthalmologic clinic. Long- and short-term PM2.5 exposed-rat models were established to investigate the changes in LSPCs and the associated mechanisms. RESULTS We found that people living in regions with higher PM2.5 concentrations had thinner limbal epithelium, indicating the loss of LSPCs. In rat models, long-term PM2.5 exposure impairs LSPCs renewal and differentiation, manifesting as corneal epithelial defects and thinner epithelium in the cornea and limbus. However, LSPCs were activated in short-term PM2.5-exposed rat models. RNA sequencing implied that the circadian rhythm in LSPCs was perturbed during PM2.5 exposure. The mRNA level of circadian genes including Per1, Per2, Per3, and Rev-erbα was upregulated in both short- and long-term models, suggesting circadian rhythm was involved in the activation and dysregulation of LSPCs at different stages. PM2.5 also disturbed the limbal microenvironment as evidenced by changes in corneal subbasal nerve fiber density, vascular density and permeability, and immune cell infiltration, which further resulted in the circadian mismatches and dysfunction of LSPCs. CONCLUSION This study systematically demonstrates that PM2.5 impairs LSPCs and their microenvironment. Moreover, we show that circadian misalignment of LSPCs may be a new mechanism by which PM2.5 induces corneal diseases. Therapeutic options that target circadian rhythm may be viable options for improving LSPC functions and alleviating various PM2.5-associated corneal diseases.
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Affiliation(s)
- Shengjie Hao
- Eye Center of the 2nd Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Lab of Ophthalmology, Zhejiang University, Hangzhou, 310009, Zhejiang Province, China
| | - Zhijian Chen
- Department of Environmental and Occupational Health, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, 310051, Zhejiang Province, China
| | - Yuzhou Gu
- Eye Center of the 2nd Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Lab of Ophthalmology, Zhejiang University, Hangzhou, 310009, Zhejiang Province, China
| | - Lu Chen
- Eye Center of the 2nd Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Lab of Ophthalmology, Zhejiang University, Hangzhou, 310009, Zhejiang Province, China
| | - Feiyin Sheng
- Eye Center of the 2nd Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Lab of Ophthalmology, Zhejiang University, Hangzhou, 310009, Zhejiang Province, China
| | - Yili Xu
- Eye Center of the 2nd Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Lab of Ophthalmology, Zhejiang University, Hangzhou, 310009, Zhejiang Province, China
| | - Di Wu
- Eye Center of the 2nd Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Lab of Ophthalmology, Zhejiang University, Hangzhou, 310009, Zhejiang Province, China
| | - Yu Han
- Eye Center of the 2nd Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Lab of Ophthalmology, Zhejiang University, Hangzhou, 310009, Zhejiang Province, China
| | - Bing Lu
- Eye Center of the 2nd Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Lab of Ophthalmology, Zhejiang University, Hangzhou, 310009, Zhejiang Province, China
| | - Shuying Chen
- Eye Center of the 2nd Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Lab of Ophthalmology, Zhejiang University, Hangzhou, 310009, Zhejiang Province, China
| | - Wei Zhao
- Eye Center of the 2nd Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Lab of Ophthalmology, Zhejiang University, Hangzhou, 310009, Zhejiang Province, China
| | - Houfa Yin
- Eye Center of the 2nd Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Lab of Ophthalmology, Zhejiang University, Hangzhou, 310009, Zhejiang Province, China
| | - Xiaofeng Wang
- Department of Environmental and Occupational Health, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, 310051, Zhejiang Province, China
| | - S Amer Riazuddin
- The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Xiaoming Lou
- Department of Environmental and Occupational Health, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, 310051, Zhejiang Province, China.
| | - Qiuli Fu
- Eye Center of the 2nd Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Lab of Ophthalmology, Zhejiang University, Hangzhou, 310009, Zhejiang Province, China.
| | - Ke Yao
- Eye Center of the 2nd Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Lab of Ophthalmology, Zhejiang University, Hangzhou, 310009, Zhejiang Province, China.
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10
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Clahsen T, Hadrian K, Notara M, Schlereth SL, Howaldt A, Prokosch V, Volatier T, Hos D, Schroedl F, Kaser-Eichberger A, Heindl LM, Steven P, Bosch JJ, Steinkasserer A, Rokohl AC, Liu H, Mestanoglu M, Kashkar H, Schumacher B, Kiefer F, Schulte-Merker S, Matthaei M, Hou Y, Fassbender S, Jantsch J, Zhang W, Enders P, Bachmann B, Bock F, Cursiefen C. The novel role of lymphatic vessels in the pathogenesis of ocular diseases. Prog Retin Eye Res 2023; 96:101157. [PMID: 36759312 DOI: 10.1016/j.preteyeres.2022.101157] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 12/13/2022] [Accepted: 12/17/2022] [Indexed: 02/10/2023]
Abstract
Historically, the eye has been considered as an organ free of lymphatic vessels. In recent years, however, it became evident, that lymphatic vessels or lymphatic-like vessels contribute to several ocular pathologies at various peri- and intraocular locations. The aim of this review is to outline the pathogenetic role of ocular lymphatics, the respective molecular mechanisms and to discuss current and future therapeutic options based thereon. We will give an overview on the vascular anatomy of the healthy ocular surface and the molecular mechanisms contributing to corneal (lymph)angiogenic privilege. In addition, we present (i) current insights into the cellular and molecular mechanisms occurring during pathological neovascularization of the cornea triggered e.g. by inflammation or trauma, (ii) the role of lymphatic vessels in different ocular surface pathologies such as dry eye disease, corneal graft rejection, ocular graft versus host disease, allergy, and pterygium, (iii) the involvement of lymphatic vessels in ocular tumors and metastasis, and (iv) the novel role of the lymphatic-like structure of Schlemm's canal in glaucoma. Identification of the underlying molecular mechanisms and of novel modulators of lymphangiogenesis will contribute to the development of new therapeutic targets for the treatment of ocular diseases associated with pathological lymphangiogenesis in the future. The preclinical data presented here outline novel therapeutic concepts for promoting transplant survival, inhibiting metastasis of ocular tumors, reducing inflammation of the ocular surface, and treating glaucoma. Initial data from clinical trials suggest first success of novel treatment strategies to promote transplant survival based on pretransplant corneal lymphangioregression.
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Affiliation(s)
- Thomas Clahsen
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Karina Hadrian
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Maria Notara
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Simona L Schlereth
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Antonia Howaldt
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Verena Prokosch
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Thomas Volatier
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Deniz Hos
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Falk Schroedl
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Alexandra Kaser-Eichberger
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Ludwig M Heindl
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Philipp Steven
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Cluster of Excellence: Cellular Stress Responses in Ageing-Associated Diseases, CECAD, University of Cologne, Cologne, Germany
| | - Jacobus J Bosch
- Centre for Human Drug Research and Leiden University Medical Center, Leiden, the Netherlands
| | | | - Alexander C Rokohl
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Hanhan Liu
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Mert Mestanoglu
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Hamid Kashkar
- Institute for Molecular Immunology, Center for Molecular Medicine Cologne (CMMC), CECAD Research Center, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Björn Schumacher
- Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany; Cluster of Excellence: Cellular Stress Responses in Ageing-Associated Diseases, CECAD, University of Cologne, Cologne, Germany
| | - Friedemann Kiefer
- European Institute for Molecular Imaging (EIMI), University of Münster, 48149, Münster, Germany
| | - Stefan Schulte-Merker
- Institute for Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, Münster, Germany
| | - Mario Matthaei
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Yanhong Hou
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Xuhui District, Shanghai, China
| | - Sonja Fassbender
- IUF‒Leibniz Research Institute for Environmental Medicine, Duesseldorf, Germany; Immunology and Environment, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Jonathan Jantsch
- Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Wei Zhang
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Philip Enders
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Björn Bachmann
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Felix Bock
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Claus Cursiefen
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany; Cluster of Excellence: Cellular Stress Responses in Ageing-Associated Diseases, CECAD, University of Cologne, Cologne, Germany.
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11
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Meshko B, Volatier TLA, Hadrian K, Deng S, Hou Y, Kluth MA, Ganss C, Frank MH, Frank NY, Ksander B, Cursiefen C, Notara M. ABCB5+ Limbal Epithelial Stem Cells Inhibit Developmental but Promote Inflammatory (Lymph) Angiogenesis While Preventing Corneal Inflammation. Cells 2023; 12:1731. [PMID: 37443766 PMCID: PMC10341195 DOI: 10.3390/cells12131731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 06/16/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
The limbus, the vascularized junction between the cornea and conjunctiva, is thought to function as a barrier against corneal neovascularization. However, the exact mechanisms regulating this remain unknown. In this study, the limbal epithelial stem cell (LESC) marker ABCB5 was used to investigate the role of LESCs in corneal neovascularization. In an ABCB5KO model, a mild but significant increase of limbal lymphatic and blood vascular network complexity was observed in developing mice (4 weeks) but not in adult mice. Conversely, when using a cornea suture model, the WT animals exhibited a mild but significant increase in the number of lymphatic vessel sprouts compared to the ABCB5KO, suggesting a contextual anti-lymphangiogenic effect of ABCB5 on the limbal vasculature during development, but a pro-lymphangiogenic effect under inflammatory challenge in adulthood. In addition, conditioned media from ABCB5-positive cultured human limbal epithelial cells (ABCB5+) stimulated human blood and lymphatic endothelial cell proliferation and migration. Finally, a proteomic analysis demonstrated ABCB5+ cells have a pro(lymph)angiogenic as well as an anti-inflammatory profile. These data suggest a novel dual, context-dependent role of ABCB5+ LESCs, inhibiting developmental but promoting inflammatory (lymph)angiogenesis in adulthood and exerting anti-inflammatory effects. These findings are of high clinical relevance in relation to LESC therapy against blindness.
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Affiliation(s)
- Berbang Meshko
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
| | - Thomas L. A. Volatier
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
| | - Karina Hadrian
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
| | - Shuya Deng
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
| | - Yanhong Hou
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
| | - Mark Andreas Kluth
- TICEBA GmbH, Im Neuenheimer Feld 517, 69120 Heidelberg, Germany; (M.A.K.); (C.G.)
- RHEACELL GmbH & Co. KG, Im Neuenheimer Feld 517, 69120 Heidelberg, Germany
| | - Christoph Ganss
- TICEBA GmbH, Im Neuenheimer Feld 517, 69120 Heidelberg, Germany; (M.A.K.); (C.G.)
- RHEACELL GmbH & Co. KG, Im Neuenheimer Feld 517, 69120 Heidelberg, Germany
| | - Markus H. Frank
- Transplant Research Program, Boston Children’s Hospital, Boston, MA 02115, USA
- Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA;
- School of Medical and Health Sciences, Edith Cowan University, Perth, WA 6027, Australia
| | - Natasha Y. Frank
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA;
- Department of Medicine, VA Boston Healthcare System, Boston, MA 02132, USA
- Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Bruce Ksander
- Massachusetts Eye & Ear Infirmary, Schepens Eye Research Institute, Boston, MA 02114, USA;
| | - Claus Cursiefen
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
- Institute for Genome Stability in Ageing and Disease, CECAD Research Center, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
| | - Maria Notara
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50937 Cologne, Germany
- Institute for Genome Stability in Ageing and Disease, CECAD Research Center, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
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12
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Çetin EA, Babayiğit EH, Özdemir AY, Erfen Ş, Onur MA. Investigation of UV-treated mesenchymal stem cells in an in vitro wound model. In Vitro Cell Dev Biol Anim 2023:10.1007/s11626-023-00772-4. [PMID: 37296290 DOI: 10.1007/s11626-023-00772-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 05/09/2023] [Indexed: 06/12/2023]
Abstract
This study examines the effects of ultraviolet-induced adipose tissue-derived mesenchymal stem cells and their supernatants on wound healing regarding cell viability, percentage of wound healing, released cytokine, and growth factors. It has been reported in previous studies that mesenchymal stem cells are resistant to ultraviolet light and have a protective effect on skin cells against ultraviolet-induced damage. At the same time, there are many studies in the literature about the positive effects of cytokines and growth factors secreted by mesenchymal stem cells. Based on this information, the effects of ultraviolet-induced adipose-derived stem cells and supernatants containing their secreted cytokines and growth factors on an in vitro two-dimensional wound model created with two different cell lines were investigated in this study. It was determined from the results that the highest cell viability and the least apoptotic staining were 100 mJ in mesenchymal stem cells (**p < 0.01). Furthermore, analysis of cytokines and growth factors collected from supernatants also supported 100 mJ as the optimal ultraviolet dose. It was observed that cells treated with ultraviolet and their supernatants significantly increased cell viability and wound-healing rate over time compared to other groups. In conclusion, with this study, it has been shown that adipose-derived stem cells exposed to ultraviolet light can have an important use in wound healing, both with their potential and with the more cytokines and growth factors they secrete. However, further analysis and animal experiments should be performed before clinical use.
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Affiliation(s)
- Esin Akbay Çetin
- Department of Biology, Faculty of Science, Hacettepe University, 06800, Ankara, Turkey.
| | - Elif Hatice Babayiğit
- Department of Biology, Faculty of Science, Hacettepe University, 06800, Ankara, Turkey
| | - Alp Yiğit Özdemir
- Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Şebnem Erfen
- Department of Biology, Faculty of Science, Hacettepe University, 06800, Ankara, Turkey
| | - Mehmet Ali Onur
- Department of Biology, Faculty of Science, Hacettepe University, 06800, Ankara, Turkey
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13
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Sun D, Shi WY, Dou SQ. Single-cell RNA sequencing in cornea research: Insights into limbal stem cells and their niche regulation. World J Stem Cells 2023; 15:466-475. [PMID: 37342216 PMCID: PMC10277966 DOI: 10.4252/wjsc.v15.i5.466] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/28/2023] [Accepted: 04/17/2023] [Indexed: 05/26/2023] Open
Abstract
The corneal epithelium is composed of stratified squamous epithelial cells on the outer surface of the eye, which acts as a protective barrier and is critical for clear and stable vision. Its continuous renewal or wound healing depends on the proliferation and differentiation of limbal stem cells (LSCs), a cell population that resides at the limbus in a highly regulated niche. Dysfunction of LSCs or their niche can cause limbal stem cell deficiency, a disease that is manifested by failed epithelial wound healing or even blindness. Nevertheless, compared to stem cells in other tissues, little is known about the LSCs and their niche. With the advent of single-cell RNA sequencing, our understanding of LSC characteristics and their microenvironment has grown considerably. In this review, we summarized the current findings from single-cell studies in the field of cornea research and focused on important advancements driven by this technology, including the heterogeneity of the LSC population, novel LSC markers and regulation of the LSC niche, which will provide a reference for clinical issues such as corneal epithelial wound healing, ocular surface reconstruction and interventions for related diseases.
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Affiliation(s)
- Di Sun
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao 266000, Shandong Province, China
- Qingdao Eye Hospital of Shandong First Medical University, Qingdao 266000, Shandong Province, China
| | - Wei-Yun Shi
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao 266000, Shandong Province, China
- Eye Hospital of Shandong First Medical University, Jinan 250000, Shandong Province, China
- School of Ophthalmology, Shandong First Medical University, Qingdao 266000, Shandong Province, China
| | - Sheng-Qian Dou
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao 266000, Shandong Province, China
- Qingdao Eye Hospital of Shandong First Medical University, Qingdao 266000, Shandong Province, China
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14
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Akoto T, Cai J, Nicholas S, McCord H, Estes AJ, Xu H, Karamichos D, Liu Y. Unravelling the Impact of Cyclic Mechanical Stretch in Keratoconus-A Transcriptomic Profiling Study. Int J Mol Sci 2023; 24:7437. [PMID: 37108600 PMCID: PMC10139219 DOI: 10.3390/ijms24087437] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/04/2023] [Accepted: 04/16/2023] [Indexed: 04/29/2023] Open
Abstract
Biomechanical and molecular stresses may contribute to the pathogenesis of keratoconus (KC). We aimed to profile the transcriptomic changes in healthy primary human corneal (HCF) and KC-derived cells (HKC) combined with TGFβ1 treatment and cyclic mechanical stretch (CMS), mimicking the pathophysiological condition in KC. HCFs (n = 4) and HKCs (n = 4) were cultured in flexible-bottom collagen-coated 6-well plates treated with 0, 5, and 10 ng/mL of TGFβ1 with or without 15% CMS (1 cycle/s, 24 h) using a computer-controlled Flexcell FX-6000T Tension system. We used stranded total RNA-Seq to profile expression changes in 48 HCF/HKC samples (100 bp PE, 70-90 million reads per sample), followed by bioinformatics analysis using an established pipeline with Partek Flow software. A multi-factor ANOVA model, including KC, TGFβ1 treatment, and CMS, was used to identify differentially expressed genes (DEGs, |fold change| ≥ 1.5, FDR ≤ 0.1, CPM ≥ 10 in ≥1 sample) in HKCs (n = 24) vs. HCFs (n = 24) and those responsive to TGFβ1 and/or CMS. PANTHER classification system and the DAVID bioinformatics resources were used to identify significantly enriched pathways (FDR ≤ 0.05). Using multi-factorial ANOVA analyses, 479 DEGs were identified in HKCs vs. HCFs including TGFβ1 treatment and CMS as cofactors. Among these DEGs, 199 KC-altered genes were responsive to TGFβ1, thirteen were responsive to CMS, and six were responsive to TGFβ1 and CMS. Pathway analyses using PANTHER and DAVID indicated the enrichment of genes involved in numerous KC-relevant functions, including but not limited to degradation of extracellular matrix, inflammatory response, apoptotic processes, WNT signaling, collagen fibril organization, and cytoskeletal structure organization. TGFβ1-responsive KC DEGs were also enriched in these. CMS-responsive KC-altered genes such as OBSCN, CLU, HDAC5, AK4, ITGA10, and F2RL1 were identified. Some KC-altered genes, such as CLU and F2RL1, were identified to be responsive to both TGFβ1 and CMS. For the first time, our multi-factorial RNA-Seq study has identified many KC-relevant genes and pathways in HKCs with TGFβ1 treatment under CMS, suggesting a potential role of TGFβ1 and biomechanical stretch in KC development.
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Affiliation(s)
- Theresa Akoto
- Department of Cellular Biology & Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Jingwen Cai
- Department of Cellular Biology & Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Sarah Nicholas
- North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
- Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Hayden McCord
- Department of Cellular Biology & Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Amy J. Estes
- Department of Ophthalmology, Augusta University, Augusta, GA 30912, USA
- James & Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Hongyan Xu
- Department of Population Health Sciences, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Dimitrios Karamichos
- North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
- Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Yutao Liu
- Department of Cellular Biology & Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- James & Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
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15
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Lin X, Mekonnen T, Verma S, Zevallos-Delgado C, Singh M, Aglyamov SR, Gesteira TF, Larin KV, Coulson-Thomas VJ. Hyaluronan Modulates the Biomechanical Properties of the Cornea. Invest Ophthalmol Vis Sci 2022; 63:6. [PMID: 36478198 PMCID: PMC9733656 DOI: 10.1167/iovs.63.13.6] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Purpose Hyaluronan (HA) is a major constituent of the extracellular matrix (ECM) that has high viscosity and is essential for maintaining tissue hydration. In the cornea, HA is enriched in the limbal region and is a key component of the limbal epithelial stem cell niche. HA is upregulated after injury participating in the formation of the provisional matrix, and has a key role in regulating the wound healing process. This study investigated whether changes in the distribution of HA before and after injury affects the biomechanical properties of the cornea in vivo. Methods Corneas of wild-type (wt) mice and mice lacking enzymes involved in the biosynthesis of HA were analyzed before, immediately after, and 7 and 14 days after a corneal alkali burn (AB). The corneas were evaluated using both a ring light and fluorescein stain by in vivo confocal microscopy, optical coherence elastography (OCE), and immunostaining of corneal whole mounts. Results Our results show that wt mice and mice lacking HA synthase (Has)1 and 3 present an increase in corneal stiffness 7 and 14 days after AB without a significant increase in HA expression and absence of scarring at 14 days after AB. In contrast, mice lacking Has2 present a significant decrease in corneal stiffness, with a significant increase in HA expression and scarring at 14 days after AB. Conclusions Our findings show that the mechanical properties of the cornea are significantly modulated by changes in HA distribution following alkali burn.
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Affiliation(s)
- Xiao Lin
- College of Optometry, University of Houston, Houston, Texas, United States
| | - Taye Mekonnen
- Department of Biomedical Engineering, University of Houston, Houston, Texas, United States
| | - Sudhir Verma
- College of Optometry, University of Houston, Houston, Texas, United States,Department of Zoology, Deen Dayal Upadhyaya College, University of Delhi, Delhi, India
| | | | - Manmohan Singh
- Department of Biomedical Engineering, University of Houston, Houston, Texas, United States
| | - Salavat R. Aglyamov
- Department of Mechanical Engineering, University of Houston, Houston, Texas, United States
| | - Tarsis F. Gesteira
- College of Optometry, University of Houston, Houston, Texas, United States
| | - Kirill V. Larin
- Department of Biomedical Engineering, University of Houston, Houston, Texas, United States
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16
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Masood F, Chang JH, Akbar A, Song A, Hu WY, Azar DT, Rosenblatt MI. Therapeutic Strategies for Restoring Perturbed Corneal Epithelial Homeostasis in Limbal Stem Cell Deficiency: Current Trends and Future Directions. Cells 2022; 11:3247. [PMID: 36291115 PMCID: PMC9600167 DOI: 10.3390/cells11203247] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/11/2022] [Accepted: 10/12/2022] [Indexed: 02/03/2023] Open
Abstract
Limbal stem cells constitute an important cell population required for regeneration of the corneal epithelium. If insults to limbal stem cells or their niche are sufficiently severe, a disease known as limbal stem cell deficiency occurs. In the absence of functioning limbal stem cells, vision-compromising conjunctivalization of the corneal epithelium occurs, leading to opacification, inflammation, neovascularization, and chronic scarring. Limbal stem cell transplantation is the standard treatment for unilateral cases of limbal stem cell deficiency, but bilateral cases require allogeneic transplantation. Herein we review the current therapeutic utilization of limbal stem cells. We also describe several limbal stem cell markers that impact their phenotype and function and discuss the possibility of modulating limbal stem cells and other sources of stem cells to facilitate the development of novel therapeutic interventions. We finally consider several hurdles for widespread adoption of these proposed methodologies and discuss how they can be overcome to realize vision-restoring interventions.
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Affiliation(s)
- Faisal Masood
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Jin-Hong Chang
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Anosh Akbar
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Amy Song
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Wen-Yang Hu
- Department of Urology, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Dimitri T. Azar
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Mark I. Rosenblatt
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
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17
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Domdey M, Kluth M, Maßlo C, Ganss C, Frank M, Frank N, Coroneo M, Cursiefen C, Notara M. Consecutive dosing of UVB irradiation induces loss of ABCB5 expression and activation of EMT and fibrosis proteins in limbal epithelial cells similar to pterygium epithelium. Stem Cell Res 2022; 64:102936. [PMID: 36242878 PMCID: PMC9582195 DOI: 10.1016/j.scr.2022.102936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 07/05/2022] [Accepted: 10/03/2022] [Indexed: 11/07/2022] Open
Abstract
Pterygium pathogenesis is often attributed to a population of altered limbal stem cells, which initiate corneal invasion and drive the hyperproliferation and fibrosis associated with the disease. These cells are thought to undergo epithelial to mesenchymal transition (EMT) and to contribute to subepithelial stromal fibrosis. In this study, the presence of the novel limbal stem cell marker ABCB5 in clusters of basal epithelial pterygium cells co-expressing with P63α and P40 is reported. ABCB5-positive pterygium cells also express EMT-associated fibrosis markers including vimentin and α-SMA while their β-catenin expression is reduced. By using a novel in vitro model of two-dose UV-induced EMT activation on limbal epithelial cells, we could observe the dysregulation of EMT-related proteins including an increase of vimentin and α-SMA as well as downregulation of β-catenin in epithelial cells correlating to downregulation of ABCB5. The sequential irradiation of limbal fibroblasts also induced an increase in vimentin and α-SMA. Taken together, these data demonstrate for the first time the expression of ABCB5 in pterygium stem cell activity and EMT-related events while the involvement of limbal stem cells in pterygium pathogenesis is exhibited via sequential irradiation of limbal epithelial cells. The later in vitro approach can be used to further study the involvement of limbal epithelium UV-induced EMT in pterygium pathogenesis and help identify novel treatments against pterygium growth and recurrence.
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Affiliation(s)
- M. Domdey
- Dept. of Ophthalmology, Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital, Cologne, Germany
| | - M.A. Kluth
- TICEBA GmbH, Im Neuenheimer Feld 517, Heidelberg, Germany,RHEACELL GmbH & Co. KG, Im Neuenheimer Feld 517, Heidelberg, Germany
| | - C. Maßlo
- TICEBA GmbH, Im Neuenheimer Feld 517, Heidelberg, Germany,RHEACELL GmbH & Co. KG, Im Neuenheimer Feld 517, Heidelberg, Germany
| | - C. Ganss
- TICEBA GmbH, Im Neuenheimer Feld 517, Heidelberg, Germany,RHEACELL GmbH & Co. KG, Im Neuenheimer Feld 517, Heidelberg, Germany
| | - M.H. Frank
- Transplant Research Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA,Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA,School of Medical Sciences, Edith Cowan University, Joondalup, WA, Australia
| | - N.Y. Frank
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA,Department of Medicine, VA Boston Healthcare System, Boston, MA, USA,Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA
| | - M.T. Coroneo
- Department of Ophthalmology, University of New South Wales, Prince of Wales Hospital, Sydney, Australia,Ophthalmic Surgeons, Sydney, Australia,East Sydney Private Hospital, Sydney, Australia,Look for Life Foundation, Sydney, Australia
| | - C. Cursiefen
- Dept. of Ophthalmology, Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital, Cologne, Germany,Institute for Genome Stability in Ageing and Disease, CECAD Research Center, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany,Center for Molecular Medicine Cologne (CMMK), University of Cologne, Germany
| | - M. Notara
- Dept. of Ophthalmology, Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital, Cologne, Germany,Institute for Genome Stability in Ageing and Disease, CECAD Research Center, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany,Center for Molecular Medicine Cologne (CMMK), University of Cologne, Germany,Corresponding author at: Dept. of Ophthalmology, University of Cologne, Kerpener Straße 62, 50937 Cologne, Germany.
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18
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Kauppila M, Ståhlberg R, Francisco V, Ferreira L, Skottman H. Multi‐parametric surface plasmon resonance‐based intake quantification of label‐free light‐activated nanoparticles by therapeutic limbal stem cells for corneal blindness. NANO SELECT 2022. [DOI: 10.1002/nano.202200027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Affiliation(s)
- Maija Kauppila
- Faculty of Medicine and Health Technology Tampere University Tampere Finland
| | - Roosa Ståhlberg
- Faculty of Medicine and Health Technology Tampere University Tampere Finland
| | - Vitor Francisco
- CNC ‐ Centro de Neurociências e Biologia Celular CIBB ‐ Centro de Inovação em Biomedicina e Biotecnologia University of Coimbra Coimbra Portugal
| | - Lino Ferreira
- CNC ‐ Centro de Neurociências e Biologia Celular CIBB ‐ Centro de Inovação em Biomedicina e Biotecnologia University of Coimbra Coimbra Portugal
- Faculty of Medicine University of Coimbra Coimbra Portugal
| | - Heli Skottman
- Faculty of Medicine and Health Technology Tampere University Tampere Finland
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19
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Amin S, Jalilian E, Katz E, Frank C, Yazdanpanah G, Guaiquil VH, Rosenblatt MI, Djalilian AR. The Limbal Niche and Regenerative Strategies. Vision (Basel) 2021; 5:vision5040043. [PMID: 34698278 PMCID: PMC8544688 DOI: 10.3390/vision5040043] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 08/27/2021] [Accepted: 09/16/2021] [Indexed: 12/17/2022] Open
Abstract
The protective function and transparency provided by the corneal epithelium are dependent on and maintained by the regenerative capacity of limbal epithelial stem cells (LESCs). These LESCs are supported by the limbal niche, a specialized microenvironment consisting of cellular and non-cellular components. Disruption of the limbal niche, primarily from injuries or inflammatory processes, can negatively impact the regenerative ability of LESCs. Limbal stem cell deficiency (LSCD) directly hampers the regenerative ability of the corneal epithelium and allows the conjunctival epithelium to invade the cornea, which results in severe visual impairment. Treatment involves restoring the LESC population and functionality; however, few clinically practiced therapies currently exist. This review outlines the current understanding of the limbal niche, its pathology and the emerging approaches targeted at restoring the limbal niche. Most emerging approaches are in developmental phases but show promise for treating LSCD and accelerating corneal regeneration. Specifically, we examine cell-based therapies, bio-active extracellular matrices and soluble factor therapies in considerable depth.
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Affiliation(s)
- Sohil Amin
- Department of Ophthalmology and Visual Sciences, University of Illinois Chicago, Chicago, IL 60612, USA; (S.A.); (E.J.); (E.K.); (C.F.); (G.Y.); (V.H.G.); (M.I.R.)
| | - Elmira Jalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois Chicago, Chicago, IL 60612, USA; (S.A.); (E.J.); (E.K.); (C.F.); (G.Y.); (V.H.G.); (M.I.R.)
| | - Eitan Katz
- Department of Ophthalmology and Visual Sciences, University of Illinois Chicago, Chicago, IL 60612, USA; (S.A.); (E.J.); (E.K.); (C.F.); (G.Y.); (V.H.G.); (M.I.R.)
| | - Charlie Frank
- Department of Ophthalmology and Visual Sciences, University of Illinois Chicago, Chicago, IL 60612, USA; (S.A.); (E.J.); (E.K.); (C.F.); (G.Y.); (V.H.G.); (M.I.R.)
| | - Ghasem Yazdanpanah
- Department of Ophthalmology and Visual Sciences, University of Illinois Chicago, Chicago, IL 60612, USA; (S.A.); (E.J.); (E.K.); (C.F.); (G.Y.); (V.H.G.); (M.I.R.)
- Richard and Loan Hill Department of Bioengineering, University of Illinois Chicago, Chicago, IL 60612, USA
| | - Victor H. Guaiquil
- Department of Ophthalmology and Visual Sciences, University of Illinois Chicago, Chicago, IL 60612, USA; (S.A.); (E.J.); (E.K.); (C.F.); (G.Y.); (V.H.G.); (M.I.R.)
| | - Mark I. Rosenblatt
- Department of Ophthalmology and Visual Sciences, University of Illinois Chicago, Chicago, IL 60612, USA; (S.A.); (E.J.); (E.K.); (C.F.); (G.Y.); (V.H.G.); (M.I.R.)
| | - Ali R. Djalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois Chicago, Chicago, IL 60612, USA; (S.A.); (E.J.); (E.K.); (C.F.); (G.Y.); (V.H.G.); (M.I.R.)
- Correspondence:
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20
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[Pterygium and pinguecula]. Ophthalmologe 2021; 118:1163-1164. [PMID: 34542693 DOI: 10.1007/s00347-021-01502-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/25/2021] [Indexed: 10/20/2022]
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21
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Abdul-Al M, Kyeremeh GK, Saeinasab M, Heidari Keshel S, Sefat F. Stem Cell Niche Microenvironment: Review. Bioengineering (Basel) 2021; 8:bioengineering8080108. [PMID: 34436111 PMCID: PMC8389324 DOI: 10.3390/bioengineering8080108] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/14/2021] [Accepted: 07/16/2021] [Indexed: 12/13/2022] Open
Abstract
The cornea comprises a pool of self-regenerating epithelial cells that are crucial to preserving clarity and visibility. Limbal epithelial stem cells (LESCs), which live in a specialized stem cell niche (SCN), are crucial for the survival of the human corneal epithelium. They live at the bottom of the limbal crypts, in a physically enclosed microenvironment with a number of neighboring niche cells. Scientists also simplified features of these diverse microenvironments for more analysis in situ by designing and recreating features of different SCNs. Recent methods for regenerating the corneal epithelium after serious trauma, including burns and allergic assaults, focus mainly on regenerating the LESCs. Mesenchymal stem cells, which can transform into self-renewing and skeletal tissues, hold immense interest for tissue engineering and innovative medicinal exploration. This review summarizes all types of LESCs, identity and location of the human epithelial stem cells (HESCs), reconstruction of LSCN and artificial stem cells for self-renewal.
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Affiliation(s)
- Mohamed Abdul-Al
- Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford BD71DP, UK; (M.A.-A.); (G.K.K.)
| | - George Kumi Kyeremeh
- Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford BD71DP, UK; (M.A.-A.); (G.K.K.)
| | - Morvarid Saeinasab
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad 91779 48974, Iran;
| | - Saeed Heidari Keshel
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran 19839 69411, Iran;
| | - Farshid Sefat
- Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford BD71DP, UK; (M.A.-A.); (G.K.K.)
- Interdisciplinary Research Centre in Polymer Science & Technology (Polymer IRC), University of Bradford, Bradford BD71DP, UK
- Correspondence:
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22
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Dou S, Wang Q, Qi X, Zhang B, Jiang H, Chen S, Duan H, Lu Y, Dong J, Cao Y, Xie L, Zhou Q, Shi W. Molecular identity of human limbal heterogeneity involved in corneal homeostasis and privilege. Ocul Surf 2021; 21:206-220. [PMID: 33964410 DOI: 10.1016/j.jtos.2021.04.010] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/10/2021] [Accepted: 04/24/2021] [Indexed: 12/20/2022]
Abstract
PURPOSE The corneal limbus maintains the homeostasis, immune and angiogenic privilege of cornea. This study aimed to depict the landscape of human limbal tissues by single-cell RNA sequencing (scRNA-seq). METHODS Single cells of human limbus collected from donor corneas were subjected to 10x scRNA-seq, followed by clustering cell types through the t-distributed stochastic neighbor embedding (t-SNE) and unbiased computational informatic analysis. Immunofluorescent staining was performed using human corneas to validate the analysis results. RESULTS 47,627 cells acquired from six human limbal tissues were collected and subjected to scRNA-seq. 14 distinct clusters were identified and 8 cell types were annotated with representative markers. In-depth dissection revealed three limbal epithelial cell subtypes and refined the X-Y-Z hypothesis of corneal epithelial maintenance. We further unveiled two cell states with higher stemness (TP63+ and CCL20+ cells), and two other differentiated cell states (GPHA2+ and KRT6B + cells) in homeostatic limbal stem/progenitor cells (LSPCs) that differ in transcriptional profiles. Cell-cell communication analysis revealed the central role of LSPCs and their bidirectional regulation with various niche cells. Moreover, comparative analysis between limbus and skin deciphered the pivotal contribution of limbal immune cells, vascular and lymphatic endothelial cells to corneal immune and angiogenic privilege. CONCLUSIONS The human limbus atlas provided valuable resources and foundations for understanding corneal biology, disease and potential interventions.
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Affiliation(s)
- Shengqian Dou
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China; Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China
| | - Qun Wang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China; Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China
| | - Xia Qi
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China; Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China
| | - Bin Zhang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China; Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China
| | - Hui Jiang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China; Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China
| | - Shengwen Chen
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China; Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China
| | - Haoyun Duan
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China; Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China
| | - Yao Lu
- OE Biotech Co., Ltd, Shanghai, Shanghai, China
| | | | - Yihai Cao
- Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden
| | - Lixin Xie
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China; Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China
| | - Qingjun Zhou
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China; Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China.
| | - Weiyun Shi
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China; Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China; Eye Hospital of Shandong First Medical University, Jinan, China.
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23
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Rokohl AC, Heindl LM, Cursiefen C. [Pterygium: pathogenesis, diagnosis and treatment]. Ophthalmologe 2021; 118:749-763. [PMID: 33782734 DOI: 10.1007/s00347-021-01366-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/26/2021] [Indexed: 12/30/2022]
Abstract
The pterygium is a frequent ultraviolet (UV) light-induced focal fibrovascular proliferation of the conjunctival tissue onto the cornea. Surgical excision should be performed in the case of reduced visual acuity, progressive astigmatism, impending invasion of the optical axis and ocular surface complaints. The main factors in preventing recurrence include optimal surgical treatment by an excision combined with a free conjunctival autograft, consistent postoperative treatment with preservative-free artificial tears and topical steroids as well as long-term UV protection.
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Affiliation(s)
- Alexander C Rokohl
- Zentrum für Augenheilkunde, Universität zu Köln, Medizinische Fakultät und Uniklinik Köln, Kerpener Straße 62, 50924, Köln, Deutschland.
| | - Ludwig M Heindl
- Zentrum für Augenheilkunde, Universität zu Köln, Medizinische Fakultät und Uniklinik Köln, Kerpener Straße 62, 50924, Köln, Deutschland
| | - Claus Cursiefen
- Zentrum für Augenheilkunde, Universität zu Köln, Medizinische Fakultät und Uniklinik Köln, Kerpener Straße 62, 50924, Köln, Deutschland.,Zentrum für Molekulare Medizin Köln (ZMMK), Universität zu Köln, Köln, Deutschland
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24
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Adil MT, Henry JJ. Understanding cornea epithelial stem cells and stem cell deficiency: Lessons learned using vertebrate model systems. Genesis 2021; 59:e23411. [PMID: 33576188 DOI: 10.1002/dvg.23411] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 01/08/2021] [Accepted: 01/09/2021] [Indexed: 12/13/2022]
Abstract
Animal models have contributed greatly to our understanding of human diseases. Here, we focus on cornea epithelial stem cell (CESC) deficiency (commonly called limbal stem cell deficiency, LSCD). Corneal development, homeostasis and wound healing are supported by specific stem cells, that include the CESCs. Damage to or loss of these cells results in blindness and other debilitating ocular conditions. Here we describe the contributions from several vertebrate models toward understanding CESCs and LSCD treatments. These include both mammalian models, as well as two aquatic models, Zebrafish and the amphibian, Xenopus. Pioneering developments have been made using stem cell transplants to restore normal vision in patients with LSCD, but questions still remain about the basic biology of CESCs, including their precise cell lineages and behavior in the cornea. We describe various cell lineage tracing studies to follow their patterns of division, and the fates of their progeny during development, homeostasis, and wound healing. In addition, we present some preliminary results using the Xenopus model system. Ultimately, a more thorough understanding of these cornea cells will advance our knowledge of stem cell biology and lead to better cornea disease therapeutics.
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Affiliation(s)
- Mohd Tayyab Adil
- Department of Cell & Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
| | - Jonathan J Henry
- Department of Cell & Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
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25
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Schlereth SL, Hos D, Matthaei M, Hamrah P, Schmetterer L, O'Leary O, Ullmer C, Horstmann J, Bock F, Wacker K, Schröder H, Notara M, Haagdorens M, Nuijts RMMA, Dunker SL, Dickman MM, Fauser S, Scholl HPN, Wheeler-Schilling T, Cursiefen C. New Technologies in Clinical Trials in Corneal Diseases and Limbal Stem Cell Deficiency: Review from the European Vision Institute Special Interest Focus Group Meeting. Ophthalmic Res 2020; 64:145-167. [PMID: 32634808 DOI: 10.1159/000509954] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 06/30/2020] [Indexed: 11/19/2022]
Abstract
To discuss and evaluate new technologies for a better diagnosis of corneal diseases and limbal stem cell deficiency, the outcomes of a consensus process within the European Vision Institute (and of a workshop at the University of Cologne) are outlined. Various technologies are presented and analyzed for their potential clinical use also in defining new end points in clinical trials. The disease areas which are discussed comprise dry eye and ocular surface inflammation, imaging, and corneal neovascularization and corneal grafting/stem cell and cell transplantation. The unmet needs in the abovementioned disease areas are discussed, and realistically achievable new technologies for better diagnosis and use in clinical trials are outlined. To sum up, it can be said that there are several new technologies that can improve current diagnostics in the field of ophthalmology in the near future and will have impact on clinical trial end point design.
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Affiliation(s)
- Simona L Schlereth
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany, .,Center for Molecular Medicine (CMMC) University of Cologne, Cologne, Germany,
| | - Deniz Hos
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.,Center for Molecular Medicine (CMMC) University of Cologne, Cologne, Germany
| | - Mario Matthaei
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Pedram Hamrah
- Cornea Service and Center for Translational Ocular Immunology, New England Eye Center, Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Leopold Schmetterer
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.,SERI-NTU Advanced Ocular Engineering (STANCE), Singapore, Singapore.,Institute for Health Technologies, Nanyang Technological University, Singapore, Singapore.,School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore, Singapore.,Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.,Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria.,Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore.,Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland
| | - Olivia O'Leary
- Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | - Christoph Ullmer
- Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | - Jens Horstmann
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Felix Bock
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Katrin Wacker
- Eye Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | | | - Maria Notara
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Michel Haagdorens
- Faculty of Medicine and Health Sciences, Department of Ophthalmology, Visual Optics and Visual Rehabilitation, University of Antwerp, Antwerp, Belgium.,Department of Ophthalmology, Antwerp University Hospital, Antwerp, Belgium
| | - Rudy M M A Nuijts
- University Eye Clinic, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Suryan L Dunker
- University Eye Clinic, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Mor M Dickman
- University Eye Clinic, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Sascha Fauser
- Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | - Hendrik P N Scholl
- Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland.,Department of Ophthalmology, University of Basel, Basel, Switzerland.,Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, USA
| | - Thomas Wheeler-Schilling
- European Vision Institute EEIG, Brussels, Belgium.,Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany
| | - Claus Cursiefen
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.,Center for Molecular Medicine (CMMC) University of Cologne, Cologne, Germany
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26
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Protective Effect of Vitamin C against Infancy Rat Corneal Injury Caused by Acute UVB Irradiation. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8089273. [PMID: 32596375 PMCID: PMC7273459 DOI: 10.1155/2020/8089273] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 02/29/2020] [Accepted: 03/11/2020] [Indexed: 01/02/2023]
Abstract
Purpose Studies have shown that corneas of young children were more susceptible to Ultraviolet B (UVB) radiation damage. However, there exist limited information about the harm of UVB to eyes and preventive measures on infancy. Vitamin C as an antioxidant is widely used to prevent many diseases. Therefore, the aim of this study was to explore the protective effect of vitamin C on the cornea of infant rats with acute UVB injury. Method Thirty-six infant rats were randomly divided into three groups: control (CON) group, UVB (UVB) group, and UVB+vitamin C (UVB+VitC) group. The UVB group was exposed to UVB irradiation (8 J/cm2, 15 min/d, 7 d) and the UVB+vitamin C group suffered the same UVB irradiation treated with vitamin C at the dose of 40 mg/kg via intraperitoneal injection. Then, corneal morphology was detected in vivo and in vitro at 7 d post-UVB exposure. Furthermore, serum inflammatory factors (IL-1, IL-6, and TNF-α) and oxidative status (4-HNE and MDA) were detected by ELISA, and the expression of vascular endothelial growth factor-α (VEGF-α) and superoxide dismutase (SOD) in the cornea was detected by western blot or immunofluorescent staining. Results Slit lamp detection revealed that the area of corneal desquamation and corneal neovascularization in the UVB+VitC group was significantly less than those in the UVB group at 7 d post-UVB exposure (all p < 0.05). OCT results showed that the thickness of the central cornea in the UVB+VitC group was decreased than that in the UVB group (p < 0.05). The serum inflammatory factors (IL-1, IL-6, and TNF-α) and oxidative status (4-HNE and MDA) in the UVB group were significantly increased compared with the CON group (all p < 0.05), while those factors in the UVB+VitC group were decreased compared with those in the UVB group. Furthermore, the expression of VEGF-α in the UVB+VitC group was dramatically decreased compared with that in the UVB group (p < 0.05), and the expression of SOD2 in the UVB+VitC group was dramatically increased compared with that in the UVB group at 7 d post-UVB exposure (p < 0.05). Conclusion Vitamin C could protect infant rats from corneal injury induced by UVB via alleviating corneal edema, improving corneal inflammatory reaction, and decreasing VEGF-α expression.
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27
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Thong T, Forté CA, Hill EM, Colacino JA. Environmental exposures, stem cells, and cancer. Pharmacol Ther 2019; 204:107398. [PMID: 31376432 PMCID: PMC6881547 DOI: 10.1016/j.pharmthera.2019.107398] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 07/29/2019] [Indexed: 12/19/2022]
Abstract
An estimated 70-90% of all cancers are linked to exposure to environmental risk factors. In parallel, the number of stem cells in a tissue has been shown to be a strong predictor of risk of developing cancer in that tissue. Tumors themselves are characterized by an acquisition of "stem cell" characteristics, and a growing body of evidence points to tumors themselves being sustained and propagated by a stem cell-like population. Here, we review our understanding of the interplay between environmental exposures, stem cell biology, and cancer. We provide an overview of the role of stem cells in development, tissue homeostasis, and wound repair. We discuss the pathways and mechanisms governing stem cell plasticity and regulation of the stem cell state, and describe experimental methods for assessment of stem cells. We then review the current understanding of how environmental exposures impact stem cell function relevant to carcinogenesis and cancer prevention, with a focus on environmental and occupational exposures to chemical, physical, and biological hazards. We also highlight key areas for future research in this area, including defining whether the biological basis for cancer disparities is related to effects of complex exposure mixtures on stem cell biology.
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Affiliation(s)
- Tasha Thong
- Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA
| | - Chanese A Forté
- Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Michigan Institute for Computational Discovery and Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Evan M Hill
- Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA
| | - Justin A Colacino
- Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
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Pterygium Pathology: A Prospective Case-Control Study on Tear Film Cytokine Levels. Mediators Inflamm 2019; 2019:9416262. [PMID: 31780873 PMCID: PMC6875004 DOI: 10.1155/2019/9416262] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 09/05/2019] [Indexed: 12/31/2022] Open
Abstract
Pterygium is a common eye disease, linked to an increased exposure to UV radiation and dry environments. The associated pathology culminates in visual impairment and, in some rare cases, blindness. However, there remains a lot of uncertainty concerning the pathogenesis of this fibrovascular lesion. As the composition of the tear film provides a reflection into the pathological changes at the ocular surface, tear analysis represents an ideal approach to gain insight in the progression of disease following pterygiectomy. This study enrolled 19 patients and age/gender-matched healthy controls. Tear film levels of interleukin- (IL-) 6, IL-8, and vascular endothelial growth factor (VEGF) were investigated over time, and preoperative concentrations were linked to corneal neovascularization and pterygium size. Diminished tear film levels were found in unilateral patients who show no clinical signs of pterygium recurrence over a period of one year. Hence, our results highlight the potential of using the course of IL-6, IL-8, and VEGF levels in tears as biomarkers for recovery. In addition, when focusing on the affected eyes (i.e., primary and recurrent pterygium), we detected fold changes in preoperative cytokine concentrations to correspond with disease severity. As our proposed biomarkers did not reveal a linear relationship with corneal neovascularization nor the invasive behaviour of pterygium, no exact role in the pterygium pathology could be established. Hence, our data point to these factors being contributors rather than decisive players in the pathological processes.
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Igarashi N, Honjo M, Fujishiro T, Toyono T, Ono T, Mori Y, Miyata K, Obinata H, Aihara M. Activation of the Sphingosine 1 Phosphate-Rho Pathway in Pterygium and in Ultraviolet-Irradiated Normal Conjunctiva. Int J Mol Sci 2019; 20:ijms20194670. [PMID: 31547113 PMCID: PMC6801701 DOI: 10.3390/ijms20194670] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 09/17/2019] [Accepted: 09/18/2019] [Indexed: 01/05/2023] Open
Abstract
Sphingosine 1 phosphate (S1P) is a bioactive lipid that regulates cellular activity, including proliferation, cytoskeletal organization, migration, and fibrosis. In this study, the potential relevance of S1P–Rho signaling in pterygium formation and the effects of ultraviolet (UV) irradiation on activation of the S1P/S1P receptor axis and fibrotic responses were investigated in vitro. Expressions of the S1P2, S1P4, and S1P5 receptors were significantly higher in pterygium tissue than in normal conjunctiva, and the concentration of S1P was significantly elevated in the lysate of normal conjunctival fibroblast cell (NCFC) irradiated with UV (UV-NCFCs). RhoA activity was significantly upregulated in pterygium fibroblast cells (PFCs) and UV-NCFCs, and myosin phosphatase–Rho interacting protein (MRIP) was upregulated, and myosin phosphatase target subunit 1 (MYPT1) was downregulated in PFCs. Fibrogenic changes were significantly upregulated in both PFCs and UV-NCFCs compared to NCFCs. We found that the activation of the S1P receptor–Rho cascade was observed in pterygium tissue. Additionally, in vitro examination showed S1P–rho activation and fibrogenic changes in PFCs and UV-NCFCs. S1P elevation and the resulting upregulation of the downstream Rho signaling pathway may be important in pterygium formation; this pathway offers a potential therapeutic target for suppressing pterygium generation.
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Affiliation(s)
- Nozomi Igarashi
- Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
| | - Megumi Honjo
- Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
| | - Takashi Fujishiro
- Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
| | - Tetsuya Toyono
- Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
| | - Takashi Ono
- Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
- Miyata eye hospital, Miyazaki 885-0051, Japan.
| | - Yosai Mori
- Miyata eye hospital, Miyazaki 885-0051, Japan.
| | | | - Hideru Obinata
- Gunma University Initiative for Advanced Research (GIAR), Gunma 371-8511, Japan.
| | - Makoto Aihara
- Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
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Hos D, Matthaei M, Bock F, Maruyama K, Notara M, Clahsen T, Hou Y, Le VNH, Salabarria AC, Horstmann J, Bachmann BO, Cursiefen C. Immune reactions after modern lamellar (DALK, DSAEK, DMEK) versus conventional penetrating corneal transplantation. Prog Retin Eye Res 2019; 73:100768. [PMID: 31279005 DOI: 10.1016/j.preteyeres.2019.07.001] [Citation(s) in RCA: 181] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 07/01/2019] [Accepted: 07/02/2019] [Indexed: 12/12/2022]
Abstract
In the past decade, novel lamellar keratoplasty techniques such as Deep Anterior Lamellar Keratoplasty (DALK) for anterior keratoplasty and Descemet stripping automated endothelial keratoplasty (DSAEK)/Descemet membrane endothelial keratoplasty (DMEK) for posterior keratoplasty have been developed. DALK eliminates the possibility of endothelial allograft rejection, which is the main reason for graft failure after penetrating keratoplasty (PK). Compared to PK, the risk of endothelial graft rejection is significantly reduced after DSAEK/DMEK. Thus, with modern lamellar techniques, the clinical problem of endothelial graft rejection seems to be nearly solved in the low-risk situation. However, even with lamellar grafts there are epithelial, subepithelial and stromal immune reactions in DALK and endothelial immune reactions in DSAEK/DMEK, and not all keratoplasties can be performed in a lamellar fashion. Therefore, endothelial graft rejection in PK is still highly relevant, especially in the "high-risk" setting, where the cornea's (lymph)angiogenic and immune privilege is lost due to severe inflammation and pathological neovascularization. For these eyes, currently available treatment options are still unsatisfactory. In this review, we will describe currently used keratoplasty techniques, namely PK, DALK, DSAEK, and DMEK. We will summarize their indications, provide surgical descriptions, and comment on their complications and outcomes. Furthermore, we will give an overview on corneal transplant immunology. A specific focus will be placed on endothelial graft rejection and we will report on its incidence, clinical presentation, and current/future treatment and prevention options. Finally, we will speculate how the field of keratoplasty and prevention of corneal allograft rejection will develop in the future.
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Affiliation(s)
- Deniz Hos
- Department of Ophthalmology, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Mario Matthaei
- Department of Ophthalmology, University of Cologne, Cologne, Germany
| | - Felix Bock
- Department of Ophthalmology, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Kazuichi Maruyama
- Department of Innovative Visual Science, Graduate School of Medicine, Osaka University, Japan
| | - Maria Notara
- Department of Ophthalmology, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Thomas Clahsen
- Department of Ophthalmology, University of Cologne, Cologne, Germany
| | - Yanhong Hou
- Department of Ophthalmology, University of Cologne, Cologne, Germany
| | - Viet Nhat Hung Le
- Department of Ophthalmology, University of Cologne, Cologne, Germany; Department of Ophthalmology, Hue College of Medicine and Pharmacy, Hue University, Viet Nam
| | | | - Jens Horstmann
- Department of Ophthalmology, University of Cologne, Cologne, Germany
| | - Bjoern O Bachmann
- Department of Ophthalmology, University of Cologne, Cologne, Germany
| | - Claus Cursiefen
- Department of Ophthalmology, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
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McKay TB, Seyed-Razavi Y, Ghezzi CE, Dieckmann G, Nieland TJF, Cairns DM, Pollard RE, Hamrah P, Kaplan DL. Corneal pain and experimental model development. Prog Retin Eye Res 2019; 71:88-113. [PMID: 30453079 PMCID: PMC6690397 DOI: 10.1016/j.preteyeres.2018.11.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Revised: 11/03/2018] [Accepted: 11/13/2018] [Indexed: 12/13/2022]
Abstract
The cornea is a valuable tissue for studying peripheral sensory nerve structure and regeneration due to its avascularity, transparency, and dense innervation. Somatosensory innervation of the cornea serves to identify changes in environmental stimuli at the ocular surface, thereby promoting barrier function to protect the eye against injury or infection. Due to regulatory demands to screen ocular safety of potential chemical exposure, a need remains to develop functional human tissue models to predict ocular damage and pain using in vitro-based systems to increase throughput and minimize animal use. In this review, we summarize the anatomical and functional roles of corneal innervation in propagation of sensory input, corneal neuropathies associated with pain, and the status of current in vivo and in vitro models. Emphasis is placed on tissue engineering approaches to study the human corneal pain response in vitro with integration of proper cell types, controlled microenvironment, and high-throughput readouts to predict pain induction. Further developments in this field will aid in defining molecular signatures to distinguish acute and chronic pain triggers based on the immune response and epithelial, stromal, and neuronal interactions that occur at the ocular surface that lead to functional outcomes in the brain depending on severity and persistence of the stimulus.
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Affiliation(s)
- Tina B McKay
- Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA, 02155, USA
| | - Yashar Seyed-Razavi
- Center for Translational Ocular Immunology and Cornea Service, Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Chiara E Ghezzi
- Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA, 02155, USA
| | - Gabriela Dieckmann
- Center for Translational Ocular Immunology and Cornea Service, Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Thomas J F Nieland
- Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA, 02155, USA
| | - Dana M Cairns
- Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA, 02155, USA
| | - Rachel E Pollard
- Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA, 02155, USA
| | - Pedram Hamrah
- Center for Translational Ocular Immunology and Cornea Service, Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - David L Kaplan
- Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA, 02155, USA.
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Yazdanpanah G, Jabbehdari S, Djalilian AR. Emerging Approaches for Ocular Surface Regeneration. CURRENT OPHTHALMOLOGY REPORTS 2019; 7:1-10. [PMID: 31275736 DOI: 10.1007/s40135-019-00193-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Purpose of review In this manuscript, the recent advancements and novel approaches for regeneration of the ocular surface are summarized. Recent findings Following severe injuries, persistent inflammation can alter the rehabilitative capability of the ocular surface environment. Limbal stem cell deficiency (LSCD) is one of the most characterized ocular surface disorders mediated by deficiency and/or dysfunction of the limbal epithelial stem cells (LESCs) located in the limbal niche. Currently, the most advanced approach for revitalizing the ocular surface and limbal niche is based on transplantation of limbal tissues harboring LESCs. Emerging approaches have focused on restoring the ocular surface microenvironment using (1) cell-based therapies including cells with capabilities to support the LESCs and modulate the inflammation, e.g., mesenchymal stem cells (MSCs), (2) bio-active extracellular matrices from decellularized tissues, and/or purified/synthetic molecules to regenerate the microenvironment structure, and (3) soluble cytokine/growth factor cocktails to revive the signaling pathways. Summary Ocular surface/limbal environment revitalization provide promising approaches for regeneration of the ocular surface.
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Affiliation(s)
- Ghasem Yazdanpanah
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Sayena Jabbehdari
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Ali R Djalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, USA
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Strategies for reconstructing the limbal stem cell niche. Ocul Surf 2019; 17:230-240. [PMID: 30633966 DOI: 10.1016/j.jtos.2019.01.002] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 10/21/2018] [Accepted: 01/07/2019] [Indexed: 12/19/2022]
Abstract
The epithelial cell layer that covers the surface of the cornea provides a protective barrier while maintaining corneal transparency. The rapid and effective turnover of these epithelial cells depends, in part, on the limbal epithelial stem cells (LESCs) located in a specialized microenvironment known as the limbal niche. Many disorders affecting the regeneration of the corneal epithelium are related to deficiency and/or dysfunction of LESCs and the limbal niche. Current approaches for regenerating the corneal epithelium following significant injuries such as burns and inflammatory attacks are primarily aimed at repopulating the LESCs. This review summarizes and assesses the clinical feasibility and efficacy of current and emerging approaches for reconstruction of the limbal niche. In particular, the application of mesenchymal stem cells along with appropriate biological scaffolds appear to be promising strategies for long-term revitalization of the limbal niche.
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Notara M, Behboudifard S, Kluth MA, Maßlo C, Ganss C, Frank MH, Schumacher B, Cursiefen C. UV light-blocking contact lenses protect against short-term UVB-induced limbal stem cell niche damage and inflammation. Sci Rep 2018; 8:12564. [PMID: 30135547 PMCID: PMC6105637 DOI: 10.1038/s41598-018-30021-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 07/16/2018] [Indexed: 11/09/2022] Open
Abstract
UVB irradiation has been linked to pathogenesis of pterygium, a conjunctival tumor growing onto transparent cornea, the windscreen of the eye. Due to corneal anatomy, ambient UVB irradiation is amplified at the stem cell-containing nasal limbus. The aim of this study was to analyse the effect of a UV-blocking contact lens (UVBCL, senofilcon A, Class 1 UV blocker) on limbal epithelial cells and fibroblasts under UVB irradiation compared to a non-UVB-blocking contact lens. UVBCL prevented UVB-induced DNA damage (as assessed by cyclobutane pyrimidine dimer immunostaining) as well as a decrease in proliferation and scratch wound closure rate of both limbal epithelial and fibroblast cells. Similarly, UVBCL protected limbal epithelial cells from UVB-induced loss of their phenotype in terms of colony forming efficiency and stem cell marker expression (ABCB5, P63α, integrin β1) compared to controls. Moreover, with UVBCL pro-inflammatory cytokines such as TNFα and MCP1 remained unchanged. These data demonstrate the significance of UV-protection in preserving the limbal niche in response to at least short-term UVB. Our data support the use of UVBCL in protecting limbal niche cells, especially after limbal stem cell transplantation and in patients after pterygium surgery, to help prevent recurrences.
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Affiliation(s)
- M Notara
- Department of Ophthalmology, University of Cologne, Cologne, Germany.
| | - S Behboudifard
- Department of Ophthalmology, University of Cologne, Cologne, Germany
| | - M A Kluth
- TICEBA GmbH, Im Neuenheimer Feld 517, Heidelberg, Germany
- RHEACELL GmbH & Co. KG, Im Neuenheimer Feld 517, Heidelberg, Germany
| | - C Maßlo
- TICEBA GmbH, Im Neuenheimer Feld 517, Heidelberg, Germany
- RHEACELL GmbH & Co. KG, Im Neuenheimer Feld 517, Heidelberg, Germany
| | - C Ganss
- TICEBA GmbH, Im Neuenheimer Feld 517, Heidelberg, Germany
- RHEACELL GmbH & Co. KG, Im Neuenheimer Feld 517, Heidelberg, Germany
| | - M H Frank
- Transplant Research Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
- School of Medical Sciences, Edith Cowan University, Joondalup, WA, Australia
| | - B Schumacher
- Institute for Genome Stability in Ageing and Disease, CECAD Research Center, Joseph-Stelzmann-Str. 26, 50931, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMK), University of Cologne, Cologne, Germany
| | - C Cursiefen
- Department of Ophthalmology, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMK), University of Cologne, Cologne, Germany
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The Role of Limbal Epithelial Stem Cells in Regulating Corneal (Lymph)angiogenic Privilege and the Micromilieu of the Limbal Niche following UV Exposure. Stem Cells Int 2018; 2018:8620172. [PMID: 29853920 PMCID: PMC5964490 DOI: 10.1155/2018/8620172] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 04/18/2018] [Indexed: 12/02/2022] Open
Abstract
The cornea is a clear structure, void of blood, and lymphatic vessels, functioning as our window to the world. Limbal epithelial stem cells, occupying the area between avascular cornea and vascularized conjunctiva, have been implicated in tissue border maintenance, preventing conjunctivalisation and propagation of blood and lymphatic vessels into the cornea. Defects in limbal epithelial stem cells are linked to corneal neovascularisation, including lymphangiogenesis, chronic inflammation, conjunctivalisation, epithelial abnormalities including the presence of goblet cells, breaks in Bowman's membrane, persistent epithelial defects and ulceration, ocular surface squamous neoplasia, lipid keratopathy, pain, discomfort, and compromised vision. It has been postulated that pterygium is an example of focal limbal deficiency. Previous reports showing changes occurring in limbal epithelium during pterygium pathogenesis suggest that there is a link to stem cell damage. In this light, pterygium can serve as a model disease of UV-induced stem cell damage also characterised by corneal blood and lymphangiogenesis. This review focuses on the role of corneal and limbal epithelial cells and the stem cell niche in maintaining corneal avascularity and corneal immune privilege and how this may be deregulated following UV exposure. We present an overview of the PUBMED literature in the field as well as recent work from our laboratories.
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Chao SC, Hu DN, Roberts J, Shen X, Lee CY, Nien CW, Lin HY. Inhibition effect of curcumin on UVB-induced secretion of pro-inflammatory cytokines from corneal limbus epithelial cells. Int J Ophthalmol 2017; 10:827-833. [PMID: 28730070 DOI: 10.18240/ijo.2017.06.01] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 03/23/2017] [Indexed: 11/23/2022] Open
Abstract
AIM To study the effects of curcumin on the secretion of interleukin (IL)-6 and IL-8 by corneal limbus epithelial cells. METHODS Human corneal limbus epithelial cells were isolated and cultured from donor eyes and irradiated by UVB at different dosages with or without curcumin. MTT test was used for studying the effects of UVB and curcumin on the cell viability. The role of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathways on the UVB-induced secretion of IL-6 and IL-8 were tested by addition of their inhibitors to the culture with or without UVB-radiation. Levels of various signal pathways, IL-6 and IL-8 in the cells and in the conditioned culture medium were measured by ELISA analysis. RESULTS UVB at 20 mJ/cm2 or less and curcumin at 20 µmol/L or less did not affect the cell viability of cultured limbus epithelial cells (P>0.05). UVB irradiation at 10 and 20 mJ/cm2 induced a significant increase of secretion of IL-6 and IL-8 and upregulated NF-κB and phosphorylated MAPK pathways of cultured limbus epithelial cells (P<0.05). Various signal pathway inhibitors, including SP600125 (JNK inhibitor), SB203580 (p38 MAPK inhibitor) and BAY11-7082 (NF-κB inhibitor) significantly decreased the UVB-induced secretion of IL-6 and IL-8 secretion (P<0.05). Curcumin at 5-20 µmol/L significantly inhibited UVB-induced secretion of IL-6 and IL-8 by limbus epithelial cells in a dose-dependent manner; while curcumin alone did not affect the secretion of IL-6 and IL-8. The upregulation of NF-κB and MAPK pathways induced by UVB treatment was significantly inhibited by curcumin, suggesting that NF-κB and MAPK pathways are involved in the inhibitory effect of curcumin on UVB-induced production of IL-6 and IL-8. CONCLUSION Curcumin may be a promising agent to be explored for the prevention and treatment of pterygium.
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Affiliation(s)
- Shih-Chun Chao
- Department of Ophthalmology, Show Chwan Memorial Hospital, Changhua 50093, Taiwan, China.,Department of Electrical and Computer Engineering, National Chiao Tung University, Hsinchu 30010, Taiwan, China.,Department of Optometry, Central Taiwan University of Science and Technology, Taichung 40601, Taiwan, China
| | - Dan-Ning Hu
- Tissue Culture Center, New York Eye and Ear Infirmary of Mount Sinai, New York, NY 10003, USA.,Ichan School of Medicine in Mount Sinai, New York, NY 10029, USA
| | | | - Xilun Shen
- Tissue Culture Center, New York Eye and Ear Infirmary of Mount Sinai, New York, NY 10003, USA
| | - Chia-Yi Lee
- Department of Ophthalmology, Show Chwan Memorial Hospital, Changhua 50093, Taiwan, China
| | - Chan-Wei Nien
- Department of Ophthalmology, Show Chwan Memorial Hospital, Changhua 50093, Taiwan, China
| | - Hung-Yu Lin
- Department of Ophthalmology, Show Chwan Memorial Hospital, Changhua 50093, Taiwan, China.,Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan, China.,Department of Optometry, Chung Shan Medical University, Taichung 40201, Taiwan, China.,Department of Optometry, Yuanpei University of Medical Technology, Hsinchu 30015, Taiwan, China
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Abstract
PURPOSE OF REVIEW The aim of this review is to describe the underlying mechanisms of corneal epithelial homeostasis in addition to illustrating the vital role of the limbal epithelial stem cells (LESCs) and the limbal niche in epithelial regeneration and wound healing. RECENT FINDINGS The shedded corneal epithelial cells are constantly replenished by the LESCs which give rise to epithelial cells that proliferate, differentiate, and migrate centripetally. While some recent studies have proposed that epithelial stem cells may also be present in the central cornea, the predominant location for the stem cells is the limbus. The limbal niche is the specialized microenvironment consisting of cells, extracellular matrix, and signaling molecules that are essential for the function of LESCs. Disturbances to limbal niche can result in LESC dysfunction; therefore, limbal stem cell deficiency should also be considered a limbal niche deficiency. Current and in-development therapeutic strategies are aimed at restoring the limbal niche, by medical and/or surgical treatments, administration of trophic factors, and cell based therapies. SUMMARY The corneal epithelium is constantly replenished by LESCs that are housed within the limbal niche. The limbal niche is the primary determinant of the LESC function and novel therapeutic approaches should be focused on regeneration of this microenvironment.
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Delic NC, Lyons JG, Di Girolamo N, Halliday GM. Damaging Effects of Ultraviolet Radiation on the Cornea. Photochem Photobiol 2017; 93:920-929. [PMID: 27935054 DOI: 10.1111/php.12686] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 10/18/2016] [Indexed: 01/22/2023]
Abstract
The cornea sits at the anterior aspect of the eye and, like the skin, is highly exposed to ultraviolet radiation (UVR). The cornea blocks a significant proportion of UVB from reaching the posterior structures of the eye. However, UVA can penetrate the full thickness of the cornea, even reaching the anterior portion of the lens. Epidemiological data indicate that UVR is a contributing factor for a multitude of diseases of the cornea including pterygium, photokeratitis, climatic droplet keratopathy and ocular surface squamous neoplasia (OSSN), although the pathogenic mechanisms of each require further elucidation. UVR is a well-known genotoxic agent, and its effects have been well characterized in organs such as the skin. However, we are only beginning to identify its effects on the cornea, such as the UVR signature C → T and CC → TT transversions identified by sequencing and increased proliferative and shedding rates in response to UVR exposure. Alarmingly, a single low-dose exposure of UVR to the cornea is sufficient to elicit genetic, molecular and cellular changes, supporting the consideration of using protective measures, such as wearing sunglasses when outdoors. The aim of this review was to describe the adverse effects of UVR on the cornea.
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Affiliation(s)
- Naomi C Delic
- Discipline of Dermatology, Bosch Institute, University of Sydney, Camperdown, NSW, Australia.,Immune Imaging Program, Centenary Institute for Cancer Medicine and Cell Biology, Camperdown, NSW, Australia
| | - J Guy Lyons
- Discipline of Dermatology, Bosch Institute, University of Sydney, Camperdown, NSW, Australia.,Immune Imaging Program, Centenary Institute for Cancer Medicine and Cell Biology, Camperdown, NSW, Australia.,Sydney Head and Neck Cancer Institute, Cancer Services, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - Nick Di Girolamo
- Department of Pathology, School of Medical Sciences, University of New South Wales, Randwick, NSW, Australia
| | - Gary M Halliday
- Discipline of Dermatology, Bosch Institute, University of Sydney, Camperdown, NSW, Australia
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Pegoraro NS, Barbieri AV, Camponogara C, Mattiazzi J, Brum ES, Marchiori MC, Oliveira SM, Cruz L. Nanoencapsulation of coenzyme Q10 and vitamin E acetate protects against UVB radiation-induced skin injury in mice. Colloids Surf B Biointerfaces 2017; 150:32-40. [DOI: 10.1016/j.colsurfb.2016.11.013] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 11/03/2016] [Accepted: 11/07/2016] [Indexed: 01/10/2023]
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