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Liu Y, Li G, Jiang J, Fan S, Lu L, Wang T, Li G, Zhou W, Liu X, Li Y, Sun H, Liang L, Tang Y, Chen Y, Gu J, Li F, Fang X, Sun T, Lv A, Wang Y, Wang P, Wen T, Deng J, Liu Y, Lai M, Yu J, Liu D, Wang H, Chen M, Li L, Huang X, Shi J, Zhang X, Zhang K, Liang L, Zhang X. The genomic and epigenomic landscape of iridocorneal endothelial syndrome. Genes Dis 2025; 12:101448. [PMID: 40110489 PMCID: PMC11919576 DOI: 10.1016/j.gendis.2024.101448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 07/12/2024] [Accepted: 08/25/2024] [Indexed: 03/22/2025] Open
Abstract
Iridocorneal endothelial (ICE) syndrome is a rare, irreversibly blinding eye disease with an unknown etiology. Understanding its genomic and epigenomic landscape could aid in developing etiology-based therapies. In this study, we recruited 99 ICE patients and performed whole-genome sequencing (WGS) on 51 and genome-wide DNA methylation profiling on 48 of them. We conducted mutational burden testing on genes and noncoding regulatory regions, comparing the ICE cohort with control groups (9197 East Asians from the gnomAD database and 350 normal Chinese from our in-house cohort). Copy number variation (CNV) analysis and differential methylation of regions were also explored. We identified RP1L1 (27/51, 53%) with a significantly higher coding-altering mutational burden in the ICE cohort (p < 8.3×10-7), with mutations predominantly at chr8:10467637 (hg19). Additionally, 41 regions with significant CNVs were identified, including two regions at chr19:15783859-15791329 (hg19) and chr3:75786061-75790887 (hg19), showing copy number loss in 39 and 19 patients, respectively. We also identified 2,717 differentially methylated regions (DMRs), with hypomethylation prevalent in ICE syndrome (91.9% of DMRs). Among these, 45 recurrent hypomethylated regions (HMRs) in more than 10% of ICE patients showed differential methylation compared to normal controls. This study presents the first comprehensive genomic and epigenomic characterization of ICE syndrome, offering insights into its underlying etiology.
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Affiliation(s)
- Yaoming Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510060, China
| | - Gen Li
- Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, China
| | - Jiaxuan Jiang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510060, China
| | - Sujie Fan
- Eye Hospital (The Third Hospital of Handan), Handan, Hebei 056000, China
| | - Lan Lu
- Department of Ophthalmology, Department of Ophthalmology & Optometry, Fujian Medical University, Fuzhou, Fujian 350004, China
| | - Ting Wang
- Eye Hospital of Shandong First Medical University, State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Science, Jinan, Shandong 250000, China
| | - Guigang Li
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Wenzong Zhou
- Cangzhou Aier Eye Hospital, Cangzhou, Hebei 061000, China
| | - Xuequn Liu
- Nangchang Aier Eye Hospital, Nanchang, Jiangxi 330002, China
| | - Yingjie Li
- The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, China
| | - Hong Sun
- The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Liang Liang
- Department of Ophthalmology, Yichang Central People's Hospital, The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei 443003, China
| | - Yuhong Tang
- Kunming Huashan Eye Hospital, Kunming, Yunnan 650032, China
- Kunming Aier Eye Hospital, Kunming, Yunnan 650041, China
| | - Yang Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510060, China
| | - Jianjun Gu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510060, China
| | - Fei Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510060, China
| | - Xiuli Fang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510060, China
| | - Tao Sun
- Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Nanchang, Jiangxi 330006, China
| | - Aiguo Lv
- Eye Hospital (The Third Hospital of Handan), Handan, Hebei 056000, China
| | - Yayi Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510060, China
| | - Peiyuan Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510060, China
| | - Tao Wen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510060, China
| | - Jiayu Deng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510060, China
| | - Yuhong Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510060, China
| | - Mingying Lai
- Shenzhen Eye Hospital, Shenzhen, Guangdong 518000, China
| | - Jingni Yu
- Department of Ophthalmology, Xi'an Fourth Hospital, Xi'an, Shaanxi 710004, China
| | - Danyan Liu
- Department of Ophthalmology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China
| | - Hua Wang
- Eye Center of Xiangya Hospital, Central South University, Hunan Key Laboratory of Ophthalmology, Changsha, Hunan 410008, China
| | - Meizhu Chen
- Department of Ophthalmology, The 900th Hospital of Joint Logistic Support Force, PLA (Clinical Medical College of Fujian Medical University, Dongfang Hospital Affiliated to Xiamen University), Fuzhou, Fujian 350025, China
| | - Li Li
- Department of Ophthalmology, The People's Hospital Guangxi Zhuang Autonomous Region, Nanning, Guangxi 530021, China
| | - Xiaodan Huang
- Eye Center, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China
| | - Jingming Shi
- The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Xu Zhang
- Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Nanchang, Jiangxi 330006, China
| | - Kang Zhang
- Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, China
- Faculty of Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China
| | - Lingyi Liang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510060, China
| | - Xiulan Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510060, China
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Raut AK, Mohapatra S, SiddiquI G, Rajak SK, Sonar R, Basu S, Joshi V, Singh V. The Human Cornea: Unraveling Its Structural, Chemical, and Biochemical Complexities. Chem Biodivers 2025; 22:e202402224. [PMID: 39559954 DOI: 10.1002/cbdv.202402224] [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: 09/09/2024] [Revised: 11/18/2024] [Accepted: 11/19/2024] [Indexed: 11/20/2024]
Abstract
The cornea, the transparent part of the anterior eye, is vital for light refraction and vision. This review examines the intricate chemical and biochemical interactions essential for maintaining corneal transparency and highlights significant advancements in corneal biology. The cornea comprises five layers: the epithelium, Bowman's layer, stroma, Descemet's membrane, and endothelium, each contributing uniquely to its structure and function. The epithelium, maintained by limbal stem cells, serves as a barrier and interacts with the tear film to maintain ocular surface health. The stroma, abundant in organized collagen fibrils and regulated by proteoglycans, is crucial for corneal clarity and biomechanical integrity, whereas the endothelium regulates corneal hydration and nutrition. Recent imaging advances have improved visualization of these molecular structures, enhancing our understanding of collagen organization and cross-linking. Proteoglycans such as decorin and lumican regulate collagen spacing and hydration, directly influencing corneal clarity. Biochemical processes within the cornea involve signaling molecules, growth factors, and cytokines, which are essential for wound healing, inflammation, and injury response. Despite progress, questions remain regarding corneal wound healing mechanisms, the impact of oxidative stress, and the roles of microRNAs. This review synthesizes recent discoveries to advance our understanding of corneal physiology and biochemical functions.
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Affiliation(s)
- Arun Kumar Raut
- LV Prasad Eye Institute, Kallam Anji Reddy Campus, Centre for Ocular Regeneration, Brien Holden Eye Research Centre, Champalimaud Translational Centre for Eye Research, Hyderabad, Telangana, India
| | - Sonali Mohapatra
- LV Prasad Eye Institute, Kallam Anji Reddy Campus, Centre for Ocular Regeneration, Brien Holden Eye Research Centre, Champalimaud Translational Centre for Eye Research, Hyderabad, Telangana, India
| | - Gufran SiddiquI
- LV Prasad Eye Institute, Kallam Anji Reddy Campus, Centre for Ocular Regeneration, Brien Holden Eye Research Centre, Champalimaud Translational Centre for Eye Research, Hyderabad, Telangana, India
| | - Suraj Kumar Rajak
- LV Prasad Eye Institute, Kallam Anji Reddy Campus, Centre for Ocular Regeneration, Brien Holden Eye Research Centre, Champalimaud Translational Centre for Eye Research, Hyderabad, Telangana, India
| | - Rohini Sonar
- LV Prasad Eye Institute, Kallam Anji Reddy Campus, Centre for Ocular Regeneration, Brien Holden Eye Research Centre, Champalimaud Translational Centre for Eye Research, Hyderabad, Telangana, India
| | - Sayan Basu
- LV Prasad Eye Institute, Kallam Anji Reddy Campus, Centre for Ocular Regeneration, Brien Holden Eye Research Centre, Champalimaud Translational Centre for Eye Research, Hyderabad, Telangana, India
| | - Vineet Joshi
- LV Prasad Eye Institute, Kallam Anji Reddy Campus, Centre for Ocular Regeneration, Brien Holden Eye Research Centre, Champalimaud Translational Centre for Eye Research, Hyderabad, Telangana, India
| | - Vivek Singh
- LV Prasad Eye Institute, Kallam Anji Reddy Campus, Centre for Ocular Regeneration, Brien Holden Eye Research Centre, Champalimaud Translational Centre for Eye Research, Hyderabad, Telangana, India
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Ashraf S, Deshpande N, Cheung Q, Asabere JB, Wong RJ, Gauthier AG, Parekh M, Adhikari Y, Melangath G, Jurkunas UV. Modulation of ATM enhances DNA repair in G2/M phase of cell cycle and averts senescence in Fuchs endothelial corneal dystrophy. Commun Biol 2024; 7:1482. [PMID: 39523410 PMCID: PMC11551145 DOI: 10.1038/s42003-024-07179-1] [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: 05/02/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024] Open
Abstract
Fuchs Endothelial Corneal Dystrophy (FECD) is an aging disorder characterized by expedited loss of corneal endothelial cells (CEnCs) and heightened DNA damage compared to normal CEnCs. We previously established that ultraviolet-A (UVA) light causes DNA damage and leads to FECD phenotype in a non-genetic mouse model. Here, we demonstrate that acute treatment with chemical stressor, menadione, or physiological stressors, UVA, and catechol estrogen (4-OHE2), results in an early and increased activation of ATM-mediated DNA damage response in FECD compared to normal CEnCs. Acute stress with UVA and 4OHE2 causes (i) greater cell-cycle arrest and DNA repair in G2/M phase, and (ii) greater cytoprotective senescence in NQO1-/- compared to NQO1+/+ cells, which was reversed upon ATM inhibition. Chronic stress with UVA and 4OHE2 results in ATM-driven cell-cycle arrest in G0/G1 phase, reduced DNA repair, and cytotoxic senescence, due to sustained damage. Likewise, UVA-induced cell-cycle reentry, gamma-H2AX foci, and senescence-associated heterochromatin were reduced in Atm-null mice. Remarkably, inhibiting ATM activation with KU-55933 restored DNA repair in G2/M phase and attenuated senescence in chronic cellular model of FECD lacking NQO1. This study provides insights into understanding the pivotal role of ATM in regulating cell-cycle, DNA repair, and senescence, in oxidative-stress disorders like FECD.
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Affiliation(s)
- Shazia Ashraf
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA
| | - Neha Deshpande
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA
| | - Queenie Cheung
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA
| | - Jeffrey Boakye Asabere
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA
| | - Raymond Jeff Wong
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA
| | - Alex G Gauthier
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA
| | - Mohit Parekh
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA
| | - Yadav Adhikari
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA
| | - Geetha Melangath
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA
| | - Ula V Jurkunas
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA.
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Chen HC, Yang SF, Lee CY, Huang JY, Hsueh YJ, Sun MH, Chiang MC, Huang YS, Chu SM, Hsu JF, Liu CH, Chang CK, Chen KJ, Hwang YS, Lai CC, Huang CY, Wu WC. Corneal Endothelial Morphology and Ocular Biometric Indexes in Premature Children With and Without Retinopathy of Prematurity. Invest Ophthalmol Vis Sci 2024; 65:37. [PMID: 38780946 PMCID: PMC11127487 DOI: 10.1167/iovs.65.5.37] [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: 11/16/2023] [Accepted: 03/06/2024] [Indexed: 05/25/2024] Open
Abstract
Purpose The purpose of this study was to analyze human corneal endothelial cells (HCECs) morphology and ocular biometrics in premature (PM) children with or without retinopathy of prematurity (ROP). Methods Retrospective data on patient demographics, HCECs status, and ocular biometrics with at least 2 visits between 2016 and 2021 were reviewed. The main outcomes were endothelial cell density (ECD), coefficient of variation (CV), hexagonal cell ratio (HEX), central corneal thickness (CCT), axial length, anterior chamber depth, keratometry, corneal diameter, pupil diameter, and refraction status. Generalized estimating equation was used to evaluate the differences between PM no-ROP and ROP groups. We also analyzed the trend of ECD, CV, HEX, and CCT change with age between groups. Results The study included 173 PM patients without ROP and 139 patients with ROP. A total of 666 and 544 measurements were recorded in the PM no-ROP and ROP groups, respectively. The ROP group had higher spherical power, myopic spherical equivalent (SE), and steeper steep keratometry (K; P < 0.05). The ROP group had higher CV (P = 0.0144), lower HEX (P = 0.0012) and thicker CCT (P = 0.0035). In the HCECs parameters, the ROP group had slower ECD decrement (P < 0.0001), faster CV decrement (P = 0.0060), and faster HEX increment (P = 0.0001). A difference in corneal morphology changes between the ROP and PM no-ROP groups were prominent in patients with lower gestational age (GA) in the subgroup analysis. Conclusions Worse HCECs morphology and higher myopic status were initially observed in patients with prior ROP but not in PM patients with no-ROP. ECD and HCECs morphology improved with age, especially in patients with low GA.
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Affiliation(s)
- Hung-Chi Chen
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou, Taiwan
- Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chia-Yi Lee
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Nobel Eye Institute, Taipei, Taiwan
- Department of Ophthalmology, Jen-Ai Hospital Dali Branch, Taichung, Taiwan
| | - Jing-Yang Huang
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Yi-Jen Hsueh
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Ming-Hui Sun
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Ming-Chou Chiang
- Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
- Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Yu-Shu Huang
- Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
- Department of Psychiatrics, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Shih-Ming Chu
- Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
- Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Jen-Fu Hsu
- Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
- Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Chun-Hsiu Liu
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chao-Kai Chang
- Nobel Eye Institute, Taipei, Taiwan
- Department of Optometry, Da-Yeh University, Chunghua, Taiwan
| | - Kuan-Jen Chen
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Yih-Shiou Hwang
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chi-Chun Lai
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chung-Ying Huang
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Wei-Chi Wu
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
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Sunny SS, Lachova J, Kasparek P, Palkova M, Spoutil F, Prochazka J, Sedlacek R, Liskova P, Kozmik Z. Ovol2 promoter mutations in mice and human illuminate species-specific phenotypic divergence. Hum Mol Genet 2024; 33:491-500. [PMID: 37971355 DOI: 10.1093/hmg/ddad195] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/06/2022] [Accepted: 11/09/2023] [Indexed: 11/19/2023] Open
Abstract
Pathogenic variants in the highly conserved OVOL2 promoter region cause posterior polymorphous corneal dystrophy (PPCD) 1 by inducing an ectopic expression of the endothelial OVOL2 mRNA. Here we produced an allelic series of Ovol2 promoter mutations in the mouse model including the heterozygous c.-307T>C variant (RefSeq NM_021220.4) causing PPCD1 in humans. Despite the high evolutionary conservation of the Ovol2 promoter, only some alterations of its sequence had phenotypic consequences in mice. Four independent sequence variants in the distal part of the Ovol2 promoter had no significant effect on endothelial Ovol2 mRNA level or caused any ocular phenotype. In contrast, the mutation c.-307T>C resulted in increased Ovol2 expression in the corneal endothelium. However, only a small fraction of adult mice c.-307T>C heterozygotes developed ocular phenotypes such as irido-corneal adhesions, and corneal opacity. Interestingly, phenotypic penetrance was increased at embryonic stages. Notably, c.-307T>C mutation is located next to the Ovol1/Ovol2 transcription factor binding site. Mice carrying an allele with a deletion encompassing the Ovol2 binding site c.-307_-320del showed significant Ovol2 gene upregulation in the cornea endothelium and exhibited phenotypes similar to the c.-307T>C mutation. In conclusion, although the mutations c.-307T>C and -307_-320del lead to a comparably strong increase in endothelial Ovol2 expression as seen in PPCD1 patients, endothelial dystrophy was not observed in the mouse model, implicating species-specific differences in endothelial cell biology. Nonetheless, the emergence of dominant ocular phenotypes associated with Ovol2 promoter variants in mice implies a potential role of this gene in eye development and disease.
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Affiliation(s)
- Sweetu Susan Sunny
- Laboratory of Transcriptional Regulation, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20, Prague 4, Prague, Czech Republic
| | - Jitka Lachova
- Laboratory of Transcriptional Regulation, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20, Prague 4, Prague, Czech Republic
| | - Petr Kasparek
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, 513 Parnassus Avenue, CA 94158, San Francisco, United States
| | - Marcela Palkova
- Czech Centre for Phenogenomics and Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the CAS, Prumyslová 595, 252 50, Vestec, Czech Republic
| | - Frantisek Spoutil
- Czech Centre for Phenogenomics and Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the CAS, Prumyslová 595, 252 50, Vestec, Czech Republic
| | - Jan Prochazka
- Czech Centre for Phenogenomics and Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the CAS, Prumyslová 595, 252 50, Vestec, Czech Republic
| | - Radislav Sedlacek
- Czech Centre for Phenogenomics and Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the CAS, Prumyslová 595, 252 50, Vestec, Czech Republic
| | - Petra Liskova
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 121 08, Prague 2, Prague Czech Republic
- Department of Ophthalmology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, U Nemocnice 2, 128 08, Prague 2, Prague, Czech Republic
| | - Zbynek Kozmik
- Laboratory of Transcriptional Regulation, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20, Prague 4, Prague, Czech Republic
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Zhen T, Li Y, Guo Q, Yao S, You Y, Lei B. Pathogenicity and Function Analysis of Two Novel SLC4A11 Variants in Patients With Congenital Hereditary Endothelial Dystrophy. Transl Vis Sci Technol 2023; 12:1. [PMID: 37787991 PMCID: PMC10561774 DOI: 10.1167/tvst.12.10.1] [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: 04/12/2023] [Accepted: 08/10/2023] [Indexed: 10/04/2023] Open
Abstract
Purpose The purpose of this study was to explore the pathogenicity and function of two novel SLC4A11 variants associated with congenital hereditary endothelial dystrophy (CHED) and to study the function of a SLC4A11 (K263R) mutant in vitro. Methods Ophthalmic examinations were performed on a 28-year-old male proband with CHED. Whole-exome and Sanger sequencing were applied for mutation screening. Bioinformatics and pathogenicity analysis were performed. HEK293T cells were transfected with the plasmids of empty vector, wild-type SLC4A11, and SLC4A11 (K263R) mutant. The transfected cells were treated with SkQ1. Oxygen consumption, cellular reactive oxygen species (ROS) level, mitochondrial membrane potential, and apoptosis rate were measured. Results The proband had poor visual acuity with nystagmus since childhood. Corneal foggy opacity was evident in both eyes. Two novel SLC4A11 variants were detected. Sanger sequencing showed that the proband's father and sister carried c.1464-1G>T variant, and the proband's mother and sister carried c.788A>G (p.Lys263Arg) variant. Based on the American College of Medical Genetics (ACMG) guidelines, SLC4A11 c.1464-1G>T was pathogenic, whereas c.788A>G, p.K263R was a variant of undetermined significance. In vitro, SLC4A11 (K263R) variant increased ROS level and apoptosis rate. Decrease in mitochondrial membrane potential and oxygen consumption rate were remarkable. Furthermore, SkQ1 decreased ROS levels and apoptosis rate but increased mitochondrial membrane potential in the transfected cells. Conclusions Two novel heterozygous pathogenic variants of the SLC4A11 gene were identified in a family with CHED. The missense variant SLC4A11 (K263R) caused mitochondrial dysfunction and increased apoptosis in mutant transfected cells. In addition, SkQ1 presented a protective effect suggesting the anti-oxidant might be a novel therapeutic drug. Translational Relevance This study verified the pathogenicity of 2 novel variants in the SLC4A11 gene in a CHED family and found an anti-oxidant might be a new drug.
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Affiliation(s)
- Tianjiao Zhen
- Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China
| | - Ya Li
- Henan Branch of National Clinical Research Center for Ocular Diseases, Henan Eye Institute/Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China
| | - Qingge Guo
- Henan Branch of National Clinical Research Center for Ocular Diseases, Henan Eye Institute/Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China
| | - Shun Yao
- Henan Branch of National Clinical Research Center for Ocular Diseases, Henan Eye Institute/Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China
| | - Ya You
- Henan Branch of National Clinical Research Center for Ocular Diseases, Henan Eye Institute/Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China
| | - Bo Lei
- Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China
- Henan Branch of National Clinical Research Center for Ocular Diseases, Henan Eye Institute/Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China
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Zhu YT, Tighe S, Chen SL, Zhang Y, Chen SY, Kao WWY, Tseng SCG. Manufacturing of human corneal endothelial grafts. Ocul Surf 2023; 29:301-310. [PMID: 37268293 PMCID: PMC10529356 DOI: 10.1016/j.jtos.2023.05.004] [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: 02/06/2023] [Revised: 05/05/2023] [Accepted: 05/12/2023] [Indexed: 06/04/2023]
Abstract
PURPOSE Human corneal endothelial cells (HCECs) play a significant role in maintaining visual function. However, these cells are notorious for their limited proliferative capacity in vivo. Current treatment of corneal endothelial dysfunction resorts to corneal transplantation. Herein we describe an ex vivo engineering method to manufacture HCEC grafts suitable for transplantation through reprogramming into neural crest progenitors. METHODS HCECs were isolated by collagenase A from stripped Descemet membrane of cadaveric corneoscleral rims, and induced reprogramming via knockdown with p120 and Kaiso siRNAs on collagen IV-coated atelocollagen. Engineered HCEC grafts were released after assessing their identity, potency, viability, purity and sterility. Phase contrast was used for monitoring cell shape, graft size, and cell density. Immunostaining was used to determine the normal HCEC phenotype with expression of N-cadherin, ZO-1, ATPase, acetyl-α-tubulin, γ-tubulin, p75NTR, α-catenin, β-catenin, and F-actin. Stability of manufactured HCEC graft was evaluated after transit and storage for up to 3 weeks. The pump function of HCEC grafts was measured by lactate efflux. RESULTS One HCEC graft suitable for corneal transplantation was generated from 1/8th of the donor corneoscleral rim with normal hexagonal cell shape, density, and phenotype. The manufactured grafts were stable for up to 3 weeks at 37 °C or up to 1 week at 22 °C in MESCM medium and after transcontinental shipping at room temperature by retaining normal morphology (hexagonal, >2000 cells/mm2, >8 mm diameter), phenotype, and pump function. CONCLUSIONS This regenerative strategy through knockdown with p120 and Kaiso siRNAs can be used to manufacture HCEC grafts with normal phenotype, morphology and pump function following prolonged storage and shipping.
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Affiliation(s)
| | - Sean Tighe
- R&D Department, BioTissue, Miami, FL, 33126, USA
| | | | - Yuan Zhang
- R&D Department, BioTissue, Miami, FL, 33126, USA
| | - Szu-Yu Chen
- R&D Department, BioTissue, Miami, FL, 33126, USA
| | - Winston W Y Kao
- Department of Ophthalmology, University of Cincinnati, 2600 Clifton Ave, Cincinnati, OH, 45220, USA
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Mhatli A, Denis D, Lesueur A, Hugo J, David T, Aziz A. [Painful anisocoria in a five-year-old child: A rare diagnosis which must not be missed]. J Fr Ophtalmol 2023:S0181-5512(23)00226-7. [PMID: 37121825 DOI: 10.1016/j.jfo.2023.01.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/30/2023] [Accepted: 01/30/2023] [Indexed: 05/02/2023]
Abstract
Congenital ectropion uveae (CEU) is a rare anomaly of the embryonic development of the anterior segment of the eye. We report the case of a 5-year-old child with an undiagnosed CEU who was treated urgently for an acute angle closure attack. CASE DESCRIPTION A 5-year-old child was referred urgently for evaluation of anisocoria with mydriasis of the right eye and severe headache. Brain imaging with contrast injection was initially performed in the pediatric emergency department and ruled out central nervous system pathology. The initial examination of the right eye revealed an intraocular pressure (IOP) of 37mmHg, corneal edema, congenital ectropion uveae, mydriasis with pupillary block, a closed angle on gonioscopy, and a clear lens. The examination of the left eye was unremarkable, with no visible CEU. The initial management consisted of medical treatment with topical glaucoma drops and miotics and acetazolamide at 10mg/kg/d. Re-evaluation under general anesthesia showed persistent mydriasis and no resolution of the pupillary block. Filtering surgery was performed in the absence of a complete response to medical treatment, allowing control of IOP without drops and complete regression of the corneal edema. DISCUSSION CEU is a rare malformation, and pressure complications represent an insignificant proportion of pediatric glaucoma cases. The acute presentation of acute angle closure in this potentially blinding short-term setting, however, makes detection and management difficult in very young children in a great deal of pain. Only one similar case has been reported in the pediatric literature. CONCLUSION Acute angle closure complicating CEU is exceptional and difficult to diagnose in a pediatric context. Parents of children with this predisposing condition should be informed of the need to consult urgently when clinical signs of elevated intraocular pressure appear.
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Affiliation(s)
- A Mhatli
- Centre hospitalier universitaire de l'hôpital Nord, chemin des Bourrely, 13015 Marseille, France.
| | - D Denis
- Centre hospitalier universitaire de l'hôpital Nord, chemin des Bourrely, 13015 Marseille, France
| | - A Lesueur
- Centre hospitalier universitaire de l'hôpital Nord, chemin des Bourrely, 13015 Marseille, France
| | - J Hugo
- Centre hospitalier universitaire de l'hôpital Nord, chemin des Bourrely, 13015 Marseille, France
| | - T David
- Centre hospitalier universitaire de l'hôpital Nord, chemin des Bourrely, 13015 Marseille, France
| | - A Aziz
- Centre hospitalier universitaire de l'hôpital Nord, chemin des Bourrely, 13015 Marseille, France
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Mandal AK, Gothwal VK. Glaucoma management in congenital ectropion uveae: Surgical outcomes from a large tertiary referral center in South India. Eur J Ophthalmol 2023; 33:324-332. [PMID: 35769044 DOI: 10.1177/11206721221111595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
PURPOSE To evaluate the long-term outcomes of glaucoma management in patients with congenital ectropion uveae (CEU) over a period of three decades at a single large referral tertiary eye care center. METHODS Retrospective chart review of all patients with CEU treated surgically from 1990 to 2019 was performed. Primary combined trabeculotomy-trabeculectomy (CTT), trabeculectomy with and without mitomycin-C (MMC) (0.2 mg/mL for 1 min) and transscleral cyclophotocoagulation (TSCPC) were performed. Intraocular pressure (IOP) ≥6 and ≤16 mmHg without medications was considered as complete success and IOP≤ 16 mmHg with the use of upto 2 medications as qualified success. RESULTS A total of 26 eyes of 21 patients were identified with a median age of 7 years (range, 6 days to 19 years) at the time of glaucoma surgery. Median follow-up was 51.1 months (range, 7-244.6 months). Primary CTT was performed in 17 eyes (65%), trabeculectomy in 5 eyes (19%) with application of MMC in 2 eyes, and 3 eyes (12%) underwent TSCPC. One painful blind eye (4%) underwent evisceration. Mean IOP reduced from 30.8 ± 7.6 mmHg on a mean of 1.3 ± 0.8 glaucoma medications preoperatively to a mean IOP of 15.2 ± 5.9 mmHg (P < 0.0001) on a mean of 0.2 ± 0.5 medications postoperatively at final follow-up (P = 0.0009). Complete success was achieved in 20 eyes, and qualified success in 2 eyes. CONCLUSIONS CTT is a safe and efficacious primary procedure for management of early-onset glaucoma in CEU. Trabeculectomy with or without adjuvant MMC is a viable second line of treatment in late-onset glaucoma with CEU for IOP control.
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Affiliation(s)
- Anil K Mandal
- Jasti V Ramanamma Children's Eye Care Centre, Child Sight Institute, Hyderabad, Telangana, India.,VST Centre for Glaucoma Care, Hyderabad, Telangana, India
| | - Vijaya K Gothwal
- Meera and L B Deshpande Centre for Sight Enhancement, Institute for Vision Rehabilitation, Hyderabad, Telangana, India.,Brien Holden Centre for Eye Research - Patient Reported Outcomes Unit, 28592L V Prasad Eye Institute, Hyderabad, Telangana, India
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10
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Ying PX, Fu M, Huang C, Li ZH, Mao QY, Fu S, Jia XH, Cao YC, Hong LB, Cai LY, Guo X, Liu RB, Meng FK, Yi GG. Profile of biological characterizations and clinical application of corneal stem/progenitor cells. World J Stem Cells 2022; 14:777-797. [PMID: 36483848 PMCID: PMC9724387 DOI: 10.4252/wjsc.v14.i11.777] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 11/08/2022] [Accepted: 11/23/2022] [Indexed: 12/13/2022] Open
Abstract
Corneal stem/progenitor cells are typical adult stem/progenitor cells. The human cornea covers the front of the eyeball, which protects the eye from the outside environment while allowing vision. The location and function demand the cornea to maintain its transparency and to continuously renew its epithelial surface by replacing injured or aged cells through a rapid turnover process in which corneal stem/progenitor cells play an important role. Corneal stem/progenitor cells include mainly corneal epithelial stem cells, corneal endothelial cell progenitors and corneal stromal stem cells. Since the discovery of corneal epithelial stem cells (also known as limbal stem cells) in 1971, an increasing number of markers for corneal stem/progenitor cells have been proposed, but there is no consensus regarding the definitive markers for them. Therefore, the identification, isolation and cultivation of these cells remain challenging without a unified approach. In this review, we systematically introduce the profile of biological characterizations, such as anatomy, characteristics, isolation, cultivation and molecular markers, and clinical applications of the three categories of corneal stem/progenitor cells.
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Affiliation(s)
- Pei-Xi Ying
- Department of Ophthalmology, Zhujiang Hospital, The Second Clinical School, Southern Medical University, Guangzhou 510280, Guangdong Province, China
| | - Min Fu
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
| | - Chang Huang
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200030, China
- NHC Key Laboratory of Myopia, Fudan University, Shanghai 200030, China
- Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200030, China
| | - Zhi-Hong Li
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Lab of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou 510550, Guangdong Province, China
| | - Qing-Yi Mao
- The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Sheng Fu
- Hengyang Medical School, The University of South China, Hengyang 421001, Hunan Province, China
| | - Xu-Hui Jia
- The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Yu-Chen Cao
- The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Li-Bing Hong
- The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Li-Yang Cai
- The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Xi Guo
- Medical College of Rehabilitation, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Ru-Bing Liu
- The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Fan-ke Meng
- Emergency Department, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
| | - Guo-Guo Yi
- Department of Ophthalmology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
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11
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Alwadani S, Alward WLM, Syed NA, Bouhenni RA, Brownstein S, Edward DP. Posterior Embryotoxon Revisited: An Immunohistologic Study. Ophthalmol Glaucoma 2022; 5:396-401. [PMID: 35131519 DOI: 10.1016/j.ogla.2022.01.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 01/22/2022] [Accepted: 01/31/2022] [Indexed: 06/14/2023]
Abstract
PURPOSE This series describes the immunopathologic features of posterior embryotoxon (PE) and demonstrates that it is not an anterior displaced Schwalbe's line as commonly described, but a peripheral corneal stromal nub variable in location with abnormal extracellular matrix. DESIGN Case series. PARTICIPANTS Archived specimens from patients with PE. METHODS Sections from archived formalin-fixed, paraffin-embedded specimens (n = 9; 7 autopsy and 2 trabeculectomy specimens) were examined by light microscopy. Immunohistochemistry was performed on 5 specimens to characterize the extracellular matrix composition of PE. RESULTS Posterior embryotoxon appeared as nubs of whorled collagen extending from the corneal stroma, lined in some instances, by Descemet membrane. These nubs were located anterior to Schwalbe's line (n = 4), posteriorly (n = 1), partially embedded in the trabecular meshwork (n = 1), or at Schwalbe's line (n = 2). Qualitatively, collagen I labeling of the PE stroma was similar or weaker than the corneal stroma, whereas collagen III staining was focal and slightly more intense compared with the corneal stroma. Lumican and keratan sulfate staining was similar or less intense in PE compared with the corneal stroma. MAIN OUTCOME MEASURES Identify location of PE and its immunohistochemical features. CONCLUSIONS In contrast to the widely accepted definition of PE as a prominent, anteriorly displaced Schwalbe line, histologic evidence suggests that it is a direct extension of the corneal stroma with variable locations that may displace the attenuated Descemet membrane when located anterior to or at Schwalbe's line. Immunohistochemical examination revealed that the composition of PE's extracellular matrix was similar to corneal stroma but with some variability in staining intensity.
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Affiliation(s)
- Saeed Alwadani
- King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; Department of Ophthalmology, King Saud University School of Medicine, Riyadh, Saudi Arabia
| | - Wallace L M Alward
- Department of Ophthalmology and Visual Sciences and, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Nasreen A Syed
- Department of Ophthalmology and Visual Sciences and, University of Iowa Carver College of Medicine, Iowa City, Iowa; Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | | | - Seymour Brownstein
- Departments of Ophthalmology and of Pathology, Faculty of Medicine, University of Ottawa and The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Deepak P Edward
- King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; Department of Ophthalmology and Visual Sciences and Department of Pathology, University of Illinois at Chicago, Chicago, Illinois.
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12
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Gaca PJ, Lewandowicz M, Lipczynska-Lewandowska M, Simon M, Matos PAW, Doulis A, Rokohl AC, Heindl LM. Embryonic Development of the Orbit. Klin Monbl Augenheilkd 2022; 239:19-26. [PMID: 35120374 DOI: 10.1055/a-1709-1310] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
The embryonic and fetal development of the orbit comprises a series of sequential events, starting with the fertilization of the ovum and extending until birth. Most of the publications dealing with orbital morphogenesis describe the sequential development of each germinal layer, the ectoderm with its neuroectoderm derivative and the mesoderm. This approach provides a clear understanding of the mode of development of each layer but does not give the reader a general picture of the structure of the orbit within any specified time frame. In order to enhance our understanding of the developmental anatomy of the orbit, the authors have summarized the recent developments in orbital morphogenesis, a temporally precise and morphogenetically intricate process. Understanding this multidimensional process of development in prenatal life, identifying and linking signaling cascades, as well as the regulatory genes linked to existing diseases, may pave the way for advanced molecular diagnostic testing, developing minimally invasive interventions, and the use of progenitor/stem cell and even regenerative therapy.
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Affiliation(s)
- Piotr Jakub Gaca
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Michael Lewandowicz
- Department of Oncological Surgery, Multidisciplinary M. Copernicus Voivodeship Center for Oncology and Traumatology, Lodz, Poland
| | - Malgorzata Lipczynska-Lewandowska
- Clinic and Policlinic of Dental and Maxillofacial Surgery, Central Clinical Hospital of the Medical University of Lodz, Lodz, Poland
| | - Michael Simon
- Center for Integrated Oncology (CIO) Aachen - Bonn - Cologne, Duesseldorf, Cologne, Germany
| | - Philomena A Wawer Matos
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Alexandros Doulis
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Alexander C Rokohl
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Ludwig M Heindl
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.,Center for Integrated Oncology (CIO) Aachen - Bonn - Cologne, Duesseldorf, Cologne, Germany
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13
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Hussain NA, Figueiredo FC, Connon CJ. Use of biomaterials in corneal endothelial repair. Ther Adv Ophthalmol 2022; 13:25158414211058249. [PMID: 34988369 PMCID: PMC8721373 DOI: 10.1177/25158414211058249] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 10/08/2021] [Indexed: 11/20/2022] Open
Abstract
Human corneal endothelium (HCE) is a single layer of hexagonal cells that lines the posterior surface of the cornea. It forms the barrier that separates the aqueous humor from the rest of the corneal layers (stroma and epithelium layer). This layer plays a fundamental role in maintaining the hydration and transparency of the cornea, which in turn ensures a clear vision. In vivo, human corneal endothelial cells (HCECs) are generally believed to be nonproliferating. In many cases, due to their nonproliferative nature, any damage to these cells can lead to further issues with Descemet’s membrane (DM), stroma and epithelium which may ultimately lead to hazy vision and blindness. Endothelial keratoplasties such as Descemet’s stripping automated endothelial keratoplasty (DSAEK) and Descemet’s membrane endothelial keratoplasty (DEK) are the standard surgeries routinely used to restore vision following endothelial failure. Basically, these two similar surgical techniques involve the replacement of the diseased endothelial layer in the center of the cornea by a healthy layer taken from a donor cornea. Globally, eye banks are facing an increased demand to provide corneas that have suitable features for transplantation. Consequently, it can be stated that there is a significant shortage of corneal grafting tissue; for every 70 corneas required, only 1 is available. Nowadays, eye banks face long waiting lists due to shortage of donors, seriously aggravated when compared with previous years, due to the global COVID-19 pandemic. Thus, there is an urgent need to find alternative and more sustainable sources for treating endothelial diseases, such as utilizing bioengineering to use of biomaterials as a remedy. The current review focuses on the use of biomaterials to repair the corneal endothelium. A range of biomaterials have been considered based on their promising results and outstanding features, including previous studies and their key findings in the context of each biomaterial.
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Affiliation(s)
- Noor Ahmed Hussain
- University of Jeddah, Jeddah, Saudi ArabiaBiosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Francisco C Figueiredo
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UKDepartment of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Che J Connon
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
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Overview of Congenital Corneal Opacities: Clinical Diagnosis, Treatment, and Prognosis. Int Ophthalmol Clin 2022; 62:1-13. [PMID: 34965222 DOI: 10.1097/iio.0000000000000395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Chen J, Ou Q, Wang Z, Liu Y, Hu S, Liu Y, Tian H, Xu J, Gao F, Lu L, Jin C, Xu GT, Cui HP. Small-Molecule Induction Promotes Corneal Endothelial Cell Differentiation From Human iPS Cells. Front Bioeng Biotechnol 2021; 9:788987. [PMID: 34976977 PMCID: PMC8714889 DOI: 10.3389/fbioe.2021.788987] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 11/25/2021] [Indexed: 12/13/2022] Open
Abstract
Purpose: Corneal endothelial cells (CECs) serve as a barrier and foothold for the corneal stroma to maintain the function and transparency of the cornea. Loss of CECs during aging or disease states leads to blindness, and cell replacement therapy using either donated or artificially differentiated CECs remains the only curative approach. Methods: Human induced pluripotent stem cells (hiPSCs) that were cultured in chemically defined medium were induced with dual-SMAD inhibition to differentiate into neural crest cells (NCCs). A small-molecule library was screened to differentiate the NCCs into corneal endothelial-like cells. The characteristics of these cells were identified with real-time PCR and immunofluorescence. Western blotting was applied to detect the signaling pathways and key factors regulated by the small molecules. Results: We developed an effective protocol to differentiate hiPSCs into CECs with defined small molecules. The hiPSC-CECs were characterized by ZO-1, AQP1, Vimentin and Na+/K+-ATPase. Based on our small-molecule screen, we identified a small-molecule combination, A769662 and AT13148, that enabled the most efficient production of CECs. The combination of A769662 and AT13148 upregulated the PKA/AKT signaling pathway, FOXO1 and PITX2 to promote the conversion of NCCs to CECs. Conclusion: We established an efficient small molecule-based method to differentiate hiPSCs into corneal endothelial-like cells, which might facilitate drug discovery and the development of cell-based therapies for corneal diseases.
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Affiliation(s)
- Jie Chen
- Department of Ophthalmology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qingjian Ou
- Department of Ophthalmology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhe Wang
- Department of Ophthalmology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yifan Liu
- Department of Ophthalmology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shuqin Hu
- Department of Ophthalmology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yumeilan Liu
- Department of Ophthalmology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Haibin Tian
- Department of Ophthalmology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jingying Xu
- Department of Ophthalmology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Furong Gao
- Department of Ophthalmology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lixia Lu
- Department of Ophthalmology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, China
| | - Caixia Jin
- Department of Ophthalmology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, China
| | - Guo-Tong Xu
- Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, China
| | - Hong-Ping Cui
- Department of Ophthalmology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Kumar V, Jurkunas UV. Mitochondrial Dysfunction and Mitophagy in Fuchs Endothelial Corneal Dystrophy. Cells 2021; 10:1888. [PMID: 34440658 PMCID: PMC8392447 DOI: 10.3390/cells10081888] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 07/08/2021] [Accepted: 07/23/2021] [Indexed: 12/13/2022] Open
Abstract
Fuchs endothelial corneal dystrophy (FECD) is a genetically complex, heterogenous, age-related degenerative disease of corneal endothelial cells (CEnCs), occurring in the fifth decade of life with a higher incidence in females. It is characterized by extracellular matrix (ECM) protein deposition called corneal guttae, causing light glare and visual complaints in patients. Corneal transplantation is the only treatment option for FECD patients, which imposes a substantial socioeconomic burden. In FECD, CEnCs exhibit stress-induced senescence, oxidative stress, DNA damage, heightened reactive oxygen species (ROS) production, mitochondrial damage, and dysfunction as well as sustained endoplasmic reticulum (ER) stress. Among all of these, mitochondrial dysfunction involving altered mitochondrial bioenergetics and dynamics plays a critical role in FECD pathogenesis. Extreme stress initiates mitochondrial damage, leading to activation of autophagy, which involves clearance of damaged mitochondria called auto(mito)phagy. In this review, we discuss the role of mitochondrial dysfunction and mitophagy in FECD. This will provide insights into a novel mechanism of mitophagy in post-mitotic ocular cell loss and help us explore the potential treatment options for FECD.
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Affiliation(s)
- Varun Kumar
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, MA 02114, USA;
- Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA
| | - Ula V. Jurkunas
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, MA 02114, USA;
- Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA
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17
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Pan SH, Zhao N, Feng X, Jie Y, Jin ZB. Conversion of mouse embryonic fibroblasts into neural crest cells and functional corneal endothelia by defined small molecules. SCIENCE ADVANCES 2021; 7:7/23/eabg5749. [PMID: 34088673 PMCID: PMC8177713 DOI: 10.1126/sciadv.abg5749] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 04/20/2021] [Indexed: 05/06/2023]
Abstract
Reprogramming of somatic cells into desired functional cell types by small molecules has vast potential for developing cell replacement therapy. Here, we developed a stepwise strategy to generate chemically induced neural crest cells (ciNCCs) and chemically induced corneal endothelial cells (ciCECs) from mouse fibroblasts using defined small molecules. The ciNCCs exhibited typical NCC features and could differentiate into ciCECs using another chemical combination in vitro. The resulting ciCECs showed consistent gene expression profiles and self-renewal capacity to those of primary CECs. Notably, these ciCECs could be cultured for as long as 30 passages and still retain the CEC features in defined medium. Transplantation of these ciCECs into an animal model reversed corneal opacity. Our chemical approach for direct reprogramming of mouse fibroblasts into ciNCCs and ciCECs provides an alternative cell source for regeneration of corneal endothelia and other tissues derived from neural crest.
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Affiliation(s)
- Shao-Hui Pan
- Institute of Stem Cell Research, The Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China
| | - Ning Zhao
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Laboratory, Beijing 100730, China
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University and Capital Medical University, Beijing Tongren Hospital, Beijing 100730, China
| | - Xiang Feng
- Institute of Stem Cell Research, The Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China
| | - Ying Jie
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Laboratory, Beijing 100730, China
| | - Zi-Bing Jin
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Laboratory, Beijing 100730, China.
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University and Capital Medical University, Beijing Tongren Hospital, Beijing 100730, China
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Diagnostic accuracy of lateral cephalograms and cone-beam computed tomography for the assessment of sella turcica bridging. Am J Orthod Dentofacial Orthop 2021; 160:231-239. [PMID: 33975746 DOI: 10.1016/j.ajodo.2020.04.025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 03/01/2020] [Accepted: 04/01/2020] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The purpose of this research was to assess the diagnostic accuracy of sella turcica bridging on lateral cephalograms when compared with true sella turcica bridging determined via cone-beam computed tomography (CBCT). METHODS A cross-sectional study was conducted using CBCT images from which lateral cephalograms were generated. The study included 185 subjects (118 females and 67 males; age range, 10-30 years; mean age, 16.63 ± 4.20 years). Sella turcica landmarks and related measurements were calculated for both diagnostic modalities and analyzed by 1 examiner. Subjects were classified into 1 of 3 outcome groups: no bridging, partial bridging, and complete bridging. Diagnostic accuracy was evaluated using sensitivity, specificity, positive and negative predictive values, and receiver operator characteristic curves. RESULTS Ten patients were diagnosed as complete bridging on CBCT, whereas 31 patients were diagnosed as complete bridging on lateral cephalogram. Although the lateral cephalogram detected all subjects with complete bridging, it incorrectly classified 12% of subjects. The percent agreement between both diagnostic methods was 55.68%, with a kappa statistic of 0.22 on the right sella turcica and 0.20 on the left sella turcica, indicating fair but statistically significant agreement. The overall accuracy of lateral cephalograms as a diagnostic modality in discriminating between no bridging and partial bridging was good as determined with the area under the curve values of 0.86 and 0.85 for right and left sides, respectively. CONCLUSIONS Although lateral cephalograms overestimate patients with complete bridging compared to CBCTs, they are a suitable screening modality for accurately suggesting complete sella turcica bridging and differentiating between patients with no bridging and partial bridging.
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19
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Affiliation(s)
- David M. Cockburn
- Department of Optometry and Vision Sciences, University of Melbourne
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20
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Shiju TM, Carlos de Oliveira R, Wilson SE. 3D in vitro corneal models: A review of current technologies. Exp Eye Res 2020; 200:108213. [PMID: 32890484 DOI: 10.1016/j.exer.2020.108213] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/11/2020] [Accepted: 08/31/2020] [Indexed: 02/07/2023]
Abstract
Three-dimensional (3D) in vitro models are excellent tools for studying complex biological systems because of their physiological similarity to in vivo studies, cost-effectiveness and decreased reliance on animals. The influence of tissue microenvironment on the cells, cell-cell interaction and the cell-matrix interactions can be elucidated in 3D models, which are difficult to mimic in 2D cultures. In order to develop a 3D model, the required cell types are derived from the tissues or stem cells. A 3D tissue/organ model typically includes all the relevant cell types and the microenvironment corresponding to that tissue/organ. For instance, a full corneal 3D model is expected to have epithelial, stromal, endothelial and nerve cells, along with the extracellular matrix and membrane components associated with the cells. Although it is challenging to develop a corneal 3D model, several attempts have been made and various technologies established which closely mimic the in vivo environment. In this review, three major technologies are highlighted: organotypic cultures, organoids and 3D bioprinting. Also, several combinations of organotypic cultures, such as the epithelium and stroma or endothelium and neural cultures are discussed, along with the disease relevance and potential applications of these models. In the future, new biomaterials will likely promote better cell-cell and cell-matrix interactions in organotypic corneal cultures.
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21
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Metagenomic Deep Sequencing to Investigate for an Infectious Etiology of Iridocorneal Endothelial Syndrome. Cornea 2020; 39:1307-1310. [PMID: 32398422 DOI: 10.1097/ico.0000000000002368] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE Iridocorneal endothelial (ICE) syndrome is a group of rare ocular conditions that result from abnormal corneal endothelial cells, leading to secondary glaucoma, iris distortions, and corneal edema. The etiology of ICE is unknown, although it has been associated with viral infections, such as herpes simplex virus. In this study, we sought to identify an infectious etiology for ICE using advanced molecular techniques. METHODS Metagenomic RNA sequencing (MDS) is a high-throughput sequencing approach that can identify all pathogens in any clinical sample, including RNA viruses. Descemet membrane and aqueous fluid from patients with ICE syndrome were subjected to MDS testing. RESULTS Samples from 3 patients with ICE were analyzed. MDS was performed on the aqueous fluid of 3 patients and Descemet membrane and endothelial cell tissue from 1 patient. Viral pathogens were not identified in any of the samples. CONCLUSIONS We were unable to identify a viral etiology in the tissues of patients with the Chandler variant of ICE syndrome, although this study was limited by sample size.
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22
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Increasing Donor Endothelial Cell Pool by Culturing Cells from Discarded Pieces of Human Donor Corneas for Regenerative Treatments. J Ophthalmol 2019; 2019:2525384. [PMID: 31428467 PMCID: PMC6679880 DOI: 10.1155/2019/2525384] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 05/19/2019] [Accepted: 06/19/2019] [Indexed: 12/13/2022] Open
Abstract
Purpose To investigate if the peripheral corneal endothelium that is usually discarded after a corneal transplant could be used for endothelial cell culture. Methods Donor corneas (n = 19) with a mean age of 72 years, male : female ratio of 15 : 4, and death-to-preservation time of 10 hours were assessed for endothelial cell density (ECD) and number of dead cells before isolation. Alizarin red staining (n = 3) was performed to check the morphology of cells in the center and periphery. Descemet's membrane-endothelial complex was peeled from the center (8.25 mm) and the periphery (2.75 mm) and plated in two different wells of an 8-well chamber slide with media refreshed every alternate day. The confluence rate was monitored by microscopy. Live/dead analysis was performed (n = 3) at confluence. Tag-2A12 as a monoclonal antibody against peroxiredoxin-6 (Prdx-6) (n = 4), ZO-1 (zonula occludens-1) as a tight junction protein (n = 4), and Ki-67 as a proliferative cell marker (n = 4) were used to characterize the cells at confluence. Results At confluence, 8.25% average increase in the number of cells was observed from the central zone compared with 16.5% from the peripheral zone. Proliferation rate, hexagonality, Ki-67 positivity, and the cell area did not significantly differ between the groups (p > 0.05). All the proteins corresponding to the biomarkers tested were expressed in both the groups. Conclusions Although there are significantly fewer amounts of peripheral cells available after graft preparation for keratoplasty, these cells can still be used for endothelial cell culture due to their proliferative capability. The peripheral cells that are discarded after graft preparation can thus be utilized to increase the donor endothelial cell pool for regenerative treatments.
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23
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Ohuchi H, Sato K, Habuta M, Fujita H, Bando T. Congenital eye anomalies: More mosaic than thought? Congenit Anom (Kyoto) 2019; 59:56-73. [PMID: 30039880 DOI: 10.1111/cga.12304] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 07/16/2018] [Accepted: 07/17/2018] [Indexed: 12/13/2022]
Abstract
The eye is a sensory organ that primarily captures light and provides the sense of sight, as well as delivering non-visual light information involving biological rhythms and neurophysiological activities to the brain. Since the early 1990s, rapid advances in molecular biology have enabled the identification of developmental genes, genes responsible for human congenital diseases, and relevant genes of mutant animals with various anomalies. In this review, we first look at the development of the eye, and we highlight seminal reports regarding archetypal gene defects underlying three developmental ocular disorders in humans: (1) holoprosencephaly (HPE), with cyclopia being exhibited in the most severe cases; (2) microphthalmia, anophthalmia, and coloboma (MAC) phenotypes; and (3) anterior segment dysgenesis (ASDG), known as Peters anomaly and its related disorders. The recently developed methods, such as next-generation sequencing and genome editing techniques, have aided the discovery of gene mutations in congenital eye diseases and gene functions in normal eye development. Finally, we discuss Pax6-genome edited mosaic eyes and propose that somatic mosaicism in developmental gene mutations should be considered a causal factor for variable phenotypes, sporadic cases, and de novo mutations in human developmental disorders.
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Affiliation(s)
- Hideyo Ohuchi
- Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Keita Sato
- Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Munenori Habuta
- Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hirofumi Fujita
- Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Tetsuya Bando
- Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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24
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25
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Hara S, Kawasaki S, Yoshihara M, Winegarner A, Busch C, Tsujikawa M, Nishida K. Transcription factor TFAP2B up-regulates human corneal endothelial cell-specific genes during corneal development and maintenance. J Biol Chem 2019; 294:2460-2469. [PMID: 30552118 PMCID: PMC6378988 DOI: 10.1074/jbc.ra118.005527] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 12/07/2018] [Indexed: 12/13/2022] Open
Abstract
The corneal endothelium, which originates from the neural crest via the periocular mesenchyme (PM), is crucial for maintaining corneal transparency. The development of corneal endothelial cells (CECs) from the neural crest is accompanied by the expression of several transcription factors, but the contribution of some of these transcriptional regulators to CEC development is incompletely understood. Here, we focused on activating enhancer-binding protein 2 (TFAP2, AP-2), a neural crest-expressed transcription factor. Using semiquantitative/quantitative RT-PCR and reporter gene and biochemical assays, we found that, within the AP-2 family, the TFAP2B gene is the only one expressed in human CECs in vivo and that its expression is strongly localized to the peripheral region of the corneal endothelium. Furthermore, the TFAP2B protein was expressed both in vivo and in cultured CECs. During mouse development, TFAP2B expression began in the PM at embryonic day 11.5 and then in CECs during adulthood. siRNA-mediated knockdown of TFAP2B in CECs decreased the expression of the corneal endothelium-specific proteins type VIII collagen α2 (COL8A2) and zona pellucida glycoprotein 4 (ZP4) and suppressed cell proliferation. Of note, we also found that TFAP2B binds to the promoter of the COL8A2 and ZP4 genes. Furthermore, CECs that highly expressed ZP4 also highly expressed both TFAP2B and COL8A2 and showed high cell proliferation. These findings suggest that TFAP2B transcriptionally regulates CEC-specific genes and therefore may be an important transcriptional regulator of corneal endothelial development and homeostasis.
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Affiliation(s)
- Susumu Hara
- From the Departments of Stem Cells and Applied Medicine and
- Ophthalmology and
| | | | - Masahito Yoshihara
- Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan, and
- Department of Biosciences and Nutrition, Karolinska Institutet, Neo, 141 83 Huddinge, Sweden
| | | | | | - Motokazu Tsujikawa
- Ophthalmology and
- Division of Health Sciences Area of Medical Technology and Science, Department of Biomedical Informatics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
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26
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STAT3 signaling maintains homeostasis through a barrier function and cell survival in corneal endothelial cells. Exp Eye Res 2019; 179:132-141. [DOI: 10.1016/j.exer.2018.11.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 10/09/2018] [Accepted: 11/08/2018] [Indexed: 12/13/2022]
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27
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New Insights Into Corneal Endothelial Regeneration. CURRENT OPHTHALMOLOGY REPORTS 2019. [DOI: 10.1007/s40135-019-00197-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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28
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Zhu Q, Zhu Y, Tighe S, Liu Y, Hu M. Engineering of Human Corneal Endothelial Cells In Vitro. Int J Med Sci 2019; 16:507-512. [PMID: 31171901 PMCID: PMC6535652 DOI: 10.7150/ijms.30759] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 01/10/2019] [Indexed: 12/13/2022] Open
Abstract
Human corneal endothelial cells are responsible for controlling corneal transparency, however they are notorious for their limited proliferative capability. Thus, damage to these cells may cause irreversible blindness. Currently, the only way to cure blindness caused by corneal endothelial dysfunction is via corneal transplantation of a cadaver donor cornea with healthy corneal endothelium. Due to severe shortage of donor corneas worldwide, it has become paramount to develop human corneal endothelial grafts in vitro that can subsequently be transplanted in humans. Recently, we have reported effective expansion of human corneal endothelial cells by reprogramming the cells into progenitor status through use of p120-Kaiso siRNA knockdown. This new reprogramming approach circumvents the need of using induced pluripotent stem cells or embryonic stem cells. Successful promotion of this technology will encourage scientists to re-think how "contact inhibition" can safely be perturbed to our benefit, i.e., effective engineering of an in vivo-like tissue while successful maintaining the normal phenotype. In this review, we present current advances in reprogramming corneal endothelial cells in vitro, detail the methods to successful engineer human corneal endothelial grafts, and discuss their future clinical applications to cure corneal blindness.
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Affiliation(s)
- Qin Zhu
- Department of Ophthalmology, The Second People's Hospital of Yunnan Province (Fourth Affiliated Hospital of Kunming Medical University); Yunnan Eye Institute; Key Laboratory of Yunnan Province for the Prevention and Treatment of ophthalmology (2017DG008); Provincial Innovation Team for Cataract and Ocular Fundus Disease (2017HC010); Expert Workstation of Yao Ke (2017IC064), Kunming, 650021 China
| | - Yingting Zhu
- Tissue Tech, Inc., Ocular Surface Center, and Ocular Surface Research & Education Foundation, Miami, FL, 33173 USA
| | - Sean Tighe
- Tissue Tech, Inc., Ocular Surface Center, and Ocular Surface Research & Education Foundation, Miami, FL, 33173 USA
| | - Yongsong Liu
- Department of Ophthalmology, Yan' An Hospital of Kunming City, Kunming, 650051, China
| | - Min Hu
- Department of Ophthalmology, The Second People's Hospital of Yunnan Province (Fourth Affiliated Hospital of Kunming Medical University); Yunnan Eye Institute; Key Laboratory of Yunnan Province for the Prevention and Treatment of ophthalmology (2017DG008); Provincial Innovation Team for Cataract and Ocular Fundus Disease (2017HC010); Expert Workstation of Yao Ke (2017IC064), Kunming, 650021 China
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29
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Kocaba V, Damour O, Auxenfans C, Burillon C. [Corneal endothelial cell therapy, a review]. J Fr Ophtalmol 2018; 41:462-469. [PMID: 29773311 DOI: 10.1016/j.jfo.2018.01.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 01/06/2018] [Accepted: 01/09/2018] [Indexed: 02/07/2023]
Abstract
In France, endothelial dysfunction represents approximately one half of the indications for corneal transplants performed each year. However, the use of endothelial keratoplasty is limited by the technical difficulty of the procedure, a shortage of available grafts, and the potential for graft failure or rejection. These limitations are driving researchers to develop new, less invasive, and more effective therapies. Corneal endothelial cell therapy is being explored as a potential therapeutic measure, to avoid the uncertainty associated with grafting. The human cornea is an ideal tissue for cell therapy. Due to its avascular and immunologically privileged characteristics, transplanted cells are better tolerated compared with other vascularized tissues and organs. Advances in the field of stem cell engineering, particularly the development of corneal epithelial stem cell therapy for the treatment of severe ocular surface disease, have aroused a massive interest in adapting cell therapy techniques to corneal endothelial cells. This chapter, based on a review of the literature, aims at educating the reader on the latest research in the field of corneal endothelial cell therapy.
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Affiliation(s)
- V Kocaba
- Service d'ophtalmologie, pavillon C, hôpital Edouard-Herriot, 5, place d'Arsonval, 69003 Lyon, France; Université Claude-Bernard Lyon-1, 69100 Villeurbanne, France; Banque de cornée de Lyon, pavillon I, hôpital Edouard-Herriot, 5, place d'Arsonval, 69003 Lyon, France; Cornea Center of Excellence, The Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, États-Unis; Tissue Engineering and stem cell group, Singapore Eye Research Institute, 168751 Singapour.
| | - O Damour
- Banque de cornée de Lyon, pavillon I, hôpital Edouard-Herriot, 5, place d'Arsonval, 69003 Lyon, France
| | - C Auxenfans
- Banque de cornée de Lyon, pavillon I, hôpital Edouard-Herriot, 5, place d'Arsonval, 69003 Lyon, France
| | - C Burillon
- Service d'ophtalmologie, pavillon C, hôpital Edouard-Herriot, 5, place d'Arsonval, 69003 Lyon, France; Université Claude-Bernard Lyon-1, 69100 Villeurbanne, France; Banque de cornée de Lyon, pavillon I, hôpital Edouard-Herriot, 5, place d'Arsonval, 69003 Lyon, France
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30
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Feizi S. Corneal endothelial cell dysfunction: etiologies and management. Ther Adv Ophthalmol 2018; 10:2515841418815802. [PMID: 30560230 PMCID: PMC6293368 DOI: 10.1177/2515841418815802] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 10/31/2018] [Indexed: 12/13/2022] Open
Abstract
A transparent cornea is essential for the formation of a clear image on the
retina. The human cornea is arranged into well-organized layers, and each layer
plays a significant role in maintaining the transparency and viability of the
tissue. The endothelium has both barrier and pump functions, which are important
for the maintenance of corneal clarity. Many etiologies, including Fuchs’
endothelial corneal dystrophy, surgical trauma, and congenital hereditary
endothelial dystrophy, lead to endothelial cell dysfunction. The main treatment
for corneal decompensation is replacement of the abnormal corneal layers with
normal donor tissue. Nowadays, the trend is to perform selective endothelial
keratoplasty, including Descemet stripping automated endothelial keratoplasty
and Descemet’s membrane endothelial keratoplasty, to manage corneal endothelial
dysfunction. This selective approach has several advantages over penetrating
keratoplasty, including rapid recovery of visual acuity, less likelihood of
graft rejection, and better patient satisfaction. However, the global limitation
in the supply of donor corneas is becoming an increasing challenge,
necessitating alternatives to reduce this demand. Consequently, in
vitro expansion of human corneal endothelial cells is evolving as a
sustainable choice. This method is intended to prepare corneal endothelial cells
in vitro that can be transferred to the eye. Herein, we
describe the etiologies and manifestations of human corneal endothelial cell
dysfunction. We also summarize the available options for as well as recent
developments in the management of corneal endothelial dysfunction.
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Affiliation(s)
- Sepehr Feizi
- Ophthalmic Research Center, Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran 16666, Iran
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31
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Silva L, Najafi A, Suwan Y, Teekhasaenee C, Ritch R. The iridocorneal endothelial syndrome. Surv Ophthalmol 2018; 63:665-676. [DOI: 10.1016/j.survophthal.2018.01.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2017] [Revised: 12/19/2017] [Accepted: 01/08/2018] [Indexed: 02/06/2023]
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Etiological mechanism of iridocorneal endothelial (ICE) syndrome may involve infection of herpes simplex virus (HSV) and integration of viral genes into human genome. Med Hypotheses 2018; 110:50-52. [PMID: 29317068 DOI: 10.1016/j.mehy.2017.10.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 10/24/2017] [Indexed: 11/20/2022]
Abstract
Iridocorneal (ICE) syndrome is a rare ocular disease characterized by abnormal proliferation of corneal endothelial cells, progressive obstruction of irido-corneal angle and atrophy of iris. ICE syndrome progressed slowly, but can cause serious complications such as secondary glaucoma in late stage. Because the etiology of ICE syndrome is not clear, there is still no effective treatment in clinical practice. Previous studies have detected herpes simplex virus (HSV) DNA inside patient's aqueous humor. However, no further explanation for HSV-related etiology of ICE syndrome was established. Besides, construction of animal models using HSV all failed, leaving behind a blank space about how HSV infection finally led to ICE syndrome. By summarizing findings from previous studies, we came up with a hypothesis about etiology of ICE syndrome: HSV infection initiated ICE syndrome by integration of viral genetic material into human genome. Infection of HSV changed activity and morphology of endothelial cells, making them regain the ability of mitosis. Proof of such hypothesis will provide a theoretical foundation for construction of animal models and effective intervention of the disease.
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33
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Rowsey TG, Karamichos D. The role of lipids in corneal diseases and dystrophies: a systematic review. Clin Transl Med 2017; 6:30. [PMID: 28782089 PMCID: PMC5552625 DOI: 10.1186/s40169-017-0158-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 07/26/2017] [Indexed: 02/06/2023] Open
Abstract
Corneal diseases are an extensive cause of blindness worldwide and continue to persist as a challenging public health concern. Recently, various lipid-based therapies have been advocated for the modulation of corneal diseases; however, the number of studies is still very limited. Here we focus on developments and challenges on lipid-based therapies for dry eye disease, diabetic neuropathy, and Fuchs' endothelial corneal dystrophy. All three diseases are highly prevalent conditions and involve corneal stress and inflammation. Lipid-based therapeutics discussed includes cyclooxygenase inhibitors, essential fatty acids, and resolvin analogs. Lipids also show increasing promise as biomarkers of disease and are explored in this review.
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Affiliation(s)
- Tyler G. Rowsey
- University of Oklahoma, College of Medicine, Norman, OK USA
- Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
| | - Dimitrios Karamichos
- Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
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34
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Chen J, Li Z, Zhang L, Ou S, Wang Y, He X, Zou D, Jia C, Hu Q, Yang S, Li X, Li J, Wang J, Sun H, Chen Y, Zhu YT, Tseng SCG, Liu Z, Li W. Descemet's Membrane Supports Corneal Endothelial Cell Regeneration in Rabbits. Sci Rep 2017; 7:6983. [PMID: 28765543 PMCID: PMC5539296 DOI: 10.1038/s41598-017-07557-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 06/28/2017] [Indexed: 12/13/2022] Open
Abstract
Descemet’s membrane (DM) helps maintain phenotype and function of corneal endothelial cells under physiological conditions, while little is known about the function of DM in corneal endothelial wound healing process. In the current study, we performed in vivo rabbit corneal endothelial cell (CEC) injury via CEC scraping, in which DM remained intact after CECs removal, or via DM stripping, in which DM was removed together with CECs. We found rabbit corneas in the CEC scraping group healed with transparency restoration, while there was posterior fibrosis tissue formation in the corneas after DM stripping on day 14. Following CEC scraping on day 3, cells that had migrated toward the central cornea underwent a transient fibrotic endothelial-mesenchymal transition (EMT) which was reversed back to an endothelial phenotype on day 14. However, in the corneas injured via DM stripping, most of the cells in the posterior fibrosis tissue did not originate from the corneal endothelium, and they maintained fibroblastic phenotype on day 14. We concluded that corneal endothelial wound healing in rabbits has different outcomes depending upon the presence or absence of Descemet’s membrane. Descemet’s membrane supports corneal endothelial cell regeneration in rabbits after endothelial injury.
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Affiliation(s)
- Jingyao Chen
- Eye Institute of Xiamen University, Xiamen University Medical College, Xiamen, Fujian, China.,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.,Yan'an Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Zhiyuan Li
- Eye Institute of Xiamen University, Xiamen University Medical College, Xiamen, Fujian, China.,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.,The Affiliated Hospital of Southern Medicine University in Chenzhou, Chenzhou, Hunan, China
| | - Liying Zhang
- Eye Institute of Xiamen University, Xiamen University Medical College, Xiamen, Fujian, China.,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China
| | - Shangkun Ou
- Eye Institute of Xiamen University, Xiamen University Medical College, Xiamen, Fujian, China.,Xiamen University affiliated Xiamen Eye Center, Xiamen, Fujian, China.,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China
| | - Yanzi Wang
- Eye Institute of Xiamen University, Xiamen University Medical College, Xiamen, Fujian, China.,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China
| | - Xin He
- Eye Institute of Xiamen University, Xiamen University Medical College, Xiamen, Fujian, China.,Xiamen University affiliated Xiamen Eye Center, Xiamen, Fujian, China.,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China
| | - Dulei Zou
- Eye Institute of Xiamen University, Xiamen University Medical College, Xiamen, Fujian, China.,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.,Shandong Eye Hospital, Shandong Eye Institute, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Changkai Jia
- Eye Institute of Xiamen University, Xiamen University Medical College, Xiamen, Fujian, China.,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China
| | - Qianqian Hu
- Eye Institute of Xiamen University, Xiamen University Medical College, Xiamen, Fujian, China.,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China
| | - Shu Yang
- Eye Institute of Xiamen University, Xiamen University Medical College, Xiamen, Fujian, China.,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China
| | - Xian Li
- Eye Institute of Xiamen University, Xiamen University Medical College, Xiamen, Fujian, China.,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China
| | - Juan Li
- Eye Institute of Xiamen University, Xiamen University Medical College, Xiamen, Fujian, China.,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China
| | - Junqi Wang
- Eye Institute of Xiamen University, Xiamen University Medical College, Xiamen, Fujian, China.,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China
| | - Huimin Sun
- Eye Institute of Xiamen University, Xiamen University Medical College, Xiamen, Fujian, China.,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China
| | - Yongxiong Chen
- Eye Institute of Xiamen University, Xiamen University Medical College, Xiamen, Fujian, China.,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China
| | | | | | - Zuguo Liu
- Eye Institute of Xiamen University, Xiamen University Medical College, Xiamen, Fujian, China. .,Xiamen University affiliated Xiamen Eye Center, Xiamen, Fujian, China. .,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.
| | - Wei Li
- Eye Institute of Xiamen University, Xiamen University Medical College, Xiamen, Fujian, China. .,Xiamen University affiliated Xiamen Eye Center, Xiamen, Fujian, China. .,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.
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Abstract
PURPOSE To describe clinical features in children diagnosed with posterior polymorphous corneal dystrophy (PPCD) in their first or second decade of life. METHODS A retrospective study was performed with the medical records of seven unrelated Korean pediatric patients who were diagnosed with PPCD and were followed up for a minimum of 3 years. Thorough ocular examinations were performed, including best-corrected visual acuity, intraocular pressure, refractive and keratometric measurements, slit-lamp biomicroscopy, and specular microscopy at all visits. RESULTS Slit-lamp examinations revealed vesicular lesions in one patient and horizontally parallel band-like endothelial lesions in six patients. Unilateral corneal involvement was displayed in 4 patients, yielding 10 eyes with deep corneal features characteristic of PPCD. Other corneal, iris, or fundus pathologic findings were not detected in all cases. Among four children who were examined in their visual development (approximately under 8 years of age), two cases demonstrated unilateral amblyopia at initial examination and exhibited improved visual acuity after refractive correction and occlusion therapy. Astigmatism more than 1.5D, which is generally considered amblyogenic, was found in 8 among 10 PPCD-affected eyes. A final visual acuity of more than 20/32 was achieved with appropriate refractive correction in all PPCD-affected eyes. There was a negative correlation between the corneal astigmatism and the mean endothelial cell density (ECD) (r = -0.655, P = .011). Initial specular microscopic examinations revealed reduced ECD (1733.0 ± 543.9 cells/mm) composed of enlarged cells (average cell area, 624.8 ± 182.1 μm/cell) in PPCD-affected eyes, compared with those in PPCD-unaffected eyes from our study subjects (P < .001 and P = .005, respectively). A statistically significant percent loss in ECD from initial to 3 years was noted in the PPCD-affected eyes (P = .03). CONCLUSIONS The awareness and treatment of refractive error are important, especially in children with early-onset PPCD during the reversible period of amblyopia. Long-term monitoring of corneal endothelium is required in pediatric patients with early-onset PPCD based on a significant endothelial loss over 3 years in PPCD-affected eyes.
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Afshari NA, Igo RP, Morris NJ, Stambolian D, Sharma S, Pulagam VL, Dunn S, Stamler JF, Truitt BJ, Rimmler J, Kuot A, Croasdale CR, Qin X, Burdon KP, Riazuddin SA, Mills R, Klebe S, Minear MA, Zhao J, Balajonda E, Rosenwasser GO, Baratz KH, Mootha VV, Patel SV, Gregory SG, Bailey-Wilson JE, Price MO, Price FW, Craig JE, Fingert JH, Gottsch JD, Aldave AJ, Klintworth GK, Lass JH, Li YJ, Iyengar SK. Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy. Nat Commun 2017; 8:14898. [PMID: 28358029 PMCID: PMC5379100 DOI: 10.1038/ncomms14898] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 02/06/2017] [Indexed: 12/13/2022] Open
Abstract
The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal organization are highly heritable. To understand the genetic aetiology of Fuchs endothelial corneal dystrophy (FECD), the most prevalent corneal disorder requiring transplantation, we conducted a genome-wide association study (GWAS) on 1,404 FECD cases and 2,564 controls of European ancestry, followed by replication and meta-analysis, for a total of 2,075 cases and 3,342 controls. We identify three novel loci meeting genome-wide significance (P<5 × 10-8): KANK4 rs79742895, LAMC1 rs3768617 and LINC00970/ATP1B1 rs1200114. We also observe an overwhelming effect of the established TCF4 locus. Interestingly, we detect differential sex-specific association at LAMC1, with greater risk in women, and TCF4, with greater risk in men. Combining GWAS results with biological evidence we expand the knowledge of common FECD loci from one to four, and provide a deeper understanding of the underlying pathogenic basis of FECD.
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Affiliation(s)
- Natalie A. Afshari
- Shiley Eye Institute, University of California, La Jolla, California 92093, USA
| | - Robert P. Igo
- Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA
| | - Nathan J. Morris
- Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA
| | - Dwight Stambolian
- Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Shiwani Sharma
- Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, South Australia 5042, Australia
| | - V. Lakshmi Pulagam
- Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA
| | - Steven Dunn
- Michigan Cornea Consultants, PC, Southfield, Michigan 48034, USA
| | - John F. Stamler
- Department of Ophthalmology, University of Iowa, College of Medicine, Iowa City, Iowa 52242, USA
| | - Barbara J. Truitt
- Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA
| | - Jacqueline Rimmler
- Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27701, USA
| | - Abraham Kuot
- Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, South Australia 5042, Australia
| | | | - Xuejun Qin
- Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27701, USA
| | - Kathryn P. Burdon
- Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, South Australia 5042, Australia
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia
| | - S. Amer Riazuddin
- The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
| | - Richard Mills
- Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, South Australia 5042, Australia
| | - Sonja Klebe
- Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, South Australia 5042, Australia
- Department of Pathology, Flinders Medical Centre, Flinders University, Adelaide, South Australia 5042, Australia
| | - Mollie A. Minear
- Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27701, USA
| | - Jiagang Zhao
- Shiley Eye Institute, University of California, La Jolla, California 92093, USA
| | - Elmer Balajonda
- Duke University Eye Center, Duke University Medical Center, Durham, North Carolina 27710, USA
| | | | - Keith H Baratz
- Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota 55905, USA
| | - V. Vinod Mootha
- Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA
| | - Sanjay V. Patel
- Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota 55905, USA
| | - Simon G. Gregory
- Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27701, USA
| | - Joan E. Bailey-Wilson
- Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health and Johns Hopkins University, Baltimore, Maryland 21224, USA
| | | | | | - Jamie E. Craig
- Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, South Australia 5042, Australia
| | - John H. Fingert
- Department of Ophthalmology, University of Iowa, College of Medicine, Iowa City, Iowa 52242, USA
| | - John D. Gottsch
- The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
| | - Anthony J. Aldave
- Stein Eye Institute, University of California, Los Angeles, California 90095, USA
| | - Gordon K. Klintworth
- Duke University Eye Center, Duke University Medical Center, Durham, North Carolina 27710, USA
- Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA
| | - Jonathan H. Lass
- Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University and University Hospitals Eye Institute, Cleveland, Ohio 44106, USA
| | - Yi-Ju Li
- Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27701, USA
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina 27710, USA
| | - Sudha K. Iyengar
- Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University and University Hospitals Eye Institute, Cleveland, Ohio 44106, USA
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Liu Y, Sun H, Hu M, Zhu M, Tighe S, Chen S, Zhang Y, Su C, Cai S, Guo P. Human Corneal Endothelial Cells Expanded In Vitro Are a Powerful Resource for Tissue Engineering. Int J Med Sci 2017; 14:128-135. [PMID: 28260988 PMCID: PMC5332841 DOI: 10.7150/ijms.17624] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Accepted: 12/28/2016] [Indexed: 12/13/2022] Open
Abstract
Human corneal endothelial cells have two major functions: barrier function mediated by proteins such as ZO-1 and pump function mediated by Na-K-ATPase which help to maintain visual function. However, human corneal endothelial cells are notorious for their limited proliferative capability in vivo and are therefore prone to corneal endothelial dysfunction that eventually may lead to blindness. At present, the only method to cure corneal endothelial dysfunction is by transplantation of a cadaver donor cornea with normal corneal endothelial cells. Due to the global shortage of donor corneas, it is vital to engineer corneal tissue in vitro that could potentially be transplanted clinically. In this review, we summarize the advances in understanding the behavior of human corneal endothelial cells, their current engineering strategy in vitro and their potential applications.
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Affiliation(s)
- Yongsong Liu
- Department of Ophthalmology, Yan' An Hospital of Kunming City, Kunming, 650051, China
| | - Hong Sun
- Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Min Hu
- Department of Ophthalmology, the Second People's Hospital of Yunnan Province, Kunming, 650021, China
| | - Min Zhu
- Public Health, the University of Arizona, Tucson, Arizona, 85709, USA
| | - Sean Tighe
- Research and Development Department, TissueTech, Inc., 7000 SW 97th Avenue, Suite 212, Miami, FL 33173, USA
| | - Shuangling Chen
- Research and Development Department, TissueTech, Inc., 7000 SW 97th Avenue, Suite 212, Miami, FL 33173, USA
| | - Yuan Zhang
- Research and Development Department, TissueTech, Inc., 7000 SW 97th Avenue, Suite 212, Miami, FL 33173, USA
| | - Chenwei Su
- Research and Development Department, TissueTech, Inc., 7000 SW 97th Avenue, Suite 212, Miami, FL 33173, USA
| | - Subo Cai
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Ping Guo
- Shenzhen Eye Hospital, School of Optometry & Ophthalmology of Shenzhen University, Shenzhen Key Laboratory of Department of Ophthalmology, Shenzhen, 518000, China
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Liu Y, Sun H, Guo P, Hu M, Zhang Y, Tighe S, Chen S, Zhu Y. Characterization and Prospective of Human Corneal Endothelial Progenitors. Int J Med Sci 2017; 14:705-710. [PMID: 28824304 PMCID: PMC5562123 DOI: 10.7150/ijms.19018] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 04/21/2017] [Indexed: 12/15/2022] Open
Abstract
Corneal endothelial cells play a critical role in maintaining corneal transparency and dysfunction of these cells caused by aging, diseases (such as Fuch's dystrophy), injury or surgical trauma, which can lead to corneal edema and blindness. Due to their limited proliferative capacity in vivo, the only treatment method is via transplantation of a cadaver donor cornea. However, there is a severe global shortage of donor corneas. To circumvent such issues, tissue engineering of corneal tissue is a viable option thanks to the recent discoveries in this field. In this review, we summarize the recent advances in reprogramming adult human corneal endothelial cells into their progenitor status, the expansion methods and characteristics of human corneal endothelial progenitors, and their potential clinical applications as corneal endothelial cell grafts.
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Affiliation(s)
- Yongsong Liu
- Department of Ophthalmology, Yan' An Hospital of Kunming City, Kunming, 650051, China
| | - Hong Sun
- Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Ping Guo
- Shenzhen Eye Hospital, School of Optometry & Ophthalmology of Shenzhen University, Shenzhen Key Laboratory of Department of Ophthalmology, Shenzhen, 518000, China
| | - Min Hu
- Department of Ophthalmology, the Second People's Hospital of Yunnan Province, Kunming, 650021, China
| | - Yuan Zhang
- Research and Development Department, TissueTech, Inc., 7000 SW 97th Avenue, Suite 212, Miami, FL 33173, USA
| | - Sean Tighe
- Research and Development Department, TissueTech, Inc., 7000 SW 97th Avenue, Suite 212, Miami, FL 33173, USA
| | - Shuangling Chen
- Research and Development Department, TissueTech, Inc., 7000 SW 97th Avenue, Suite 212, Miami, FL 33173, USA
| | - Yingting Zhu
- Research and Development Department, TissueTech, Inc., 7000 SW 97th Avenue, Suite 212, Miami, FL 33173, USA
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Ribonuclease 5 facilitates corneal endothelial wound healing via activation of PI3-kinase/Akt pathway. Sci Rep 2016; 6:31162. [PMID: 27526633 PMCID: PMC4985649 DOI: 10.1038/srep31162] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 07/15/2016] [Indexed: 12/13/2022] Open
Abstract
To maintain corneal transparency, corneal endothelial cells (CECs) exert a pump function against aqueous inflow. However, human CECs are arrested in the G1-phase and non-proliferative in vivo. Thus, treatment of corneal endothelial decompensation is limited to corneal transplantation, and grafts are vulnerable to immune rejection. Here, we show that ribonuclease (RNase) 5 is more highly expressed in normal human CECs compared to decompensated tissues. Furthermore, RNase 5 up-regulated survival of CECs and accelerated corneal endothelial wound healing in an in vitro wound of human CECs and an in vivo cryo-damaged rabbit model. RNase 5 treatment rapidly induced accumulation of cytoplasmic RNase 5 into the nucleus, and activated PI3-kinase/Akt pathway in human CECs. Moreover, inhibition of nuclear translocation of RNase 5 using neomycin reversed RNase 5-induced Akt activation. As a potential strategy for proliferation enhancement, RNase 5 increased the population of 5-bromo-2′-deoxyuridine (BrdU)-incorporated proliferating CECs with concomitant PI3-kinase/Akt activation, especially in CECs deprived of contact-inhibition. Specifically, RNase 5 suppressed p27 and up-regulated cyclin D1, D3, and E by activating PI3-kinase/Akt in CECs to initiate cell cycle progression. Together, our data indicate that RNase 5 facilitates corneal endothelial wound healing, and identify RNase 5 as a novel target for therapeutic exploitation.
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Halilovic A, Schmedt T, Benischke AS, Hamill C, Chen Y, Santos JH, Jurkunas UV. Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy. Antioxid Redox Signal 2016; 24:1072-83. [PMID: 26935406 PMCID: PMC4931310 DOI: 10.1089/ars.2015.6532] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Revised: 02/11/2016] [Accepted: 02/29/2016] [Indexed: 12/13/2022]
Abstract
AIMS Fuchs endothelial corneal dystrophy (FECD), a leading cause of age-related corneal edema requiring transplantation, is characterized by rosette formation of corneal endothelium with ensuing apoptosis. We sought to determine whether excess of mitochondrial reactive oxygen species leads to chronic accumulation of oxidative DNA damage and mitochondrial dysfunction, instigating cell death. RESULTS We modeled the pathognomonic rosette formation of postmitotic corneal cells by increasing endogenous cellular oxidative stress with menadione (MN) and performed a temporal analysis of its effect in normal (HCEnC, HCECi) and FECD (FECDi) cells and ex vivo specimens. FECDi and FECD ex vivo specimens exhibited extensive mtDNA and nDNA damage as detected by quantitative PCR. Exposure to MN triggered an increase in mitochondrial superoxide levels and led to mtDNA and nDNA damage, while DNA amplification was restored with NAC pretreatment. Furthermore, MN exposure led to a decrease in ΔΨm and adenosine triphosphate levels in normal cells, while FECDi exhibited mitochondrial dysfunction at baseline. Mitochondrial fragmentation and cytochrome c release were detected in FECD tissue and after MN treatment of HCEnCs. Furthermore, cleavage of caspase-9 and caspase-3 followed MN-induced cytochrome c release in HCEnCs. INNOVATION This study provides the first line of evidence that accumulation of oxidative DNA damage leads to rosette formation, loss of functionally intact mitochondria via fragmentation, and subsequent cell death during postmitotic cell degeneration of ocular tissue. CONCLUSION MN induced rosette formation, along with mtDNA and nDNA damage, mitochondrial dysfunction, and fragmentation, leading to activation of the intrinsic apoptosis via caspase cleavage and cytochrome c release. Antioxid. Redox Signal. 24, 1072-1083.
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Affiliation(s)
- Adna Halilovic
- 1 Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary (MEEI), Harvard Medical School , Boston, Massachusetts
| | - Thore Schmedt
- 1 Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary (MEEI), Harvard Medical School , Boston, Massachusetts
| | - Anne-Sophie Benischke
- 1 Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary (MEEI), Harvard Medical School , Boston, Massachusetts
| | - Cecily Hamill
- 1 Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary (MEEI), Harvard Medical School , Boston, Massachusetts
| | - Yuming Chen
- 1 Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary (MEEI), Harvard Medical School , Boston, Massachusetts
| | - Janine Hertzog Santos
- 2 Department of Pharmacology and Physiology, New Jersey Medical School Rutgers, Rutgers University , New Jersey
| | - Ula V Jurkunas
- 1 Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary (MEEI), Harvard Medical School , Boston, Massachusetts
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SLC4A11 and the Pathophysiology of Congenital Hereditary Endothelial Dystrophy. BIOMED RESEARCH INTERNATIONAL 2015; 2015:475392. [PMID: 26451371 PMCID: PMC4588344 DOI: 10.1155/2015/475392] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 05/17/2015] [Indexed: 12/13/2022]
Abstract
Congenital hereditary endothelial dystrophy (CHED) is a rare autosomal recessive disorder of the corneal endothelium characterized by nonprogressive bilateral corneal edema and opacification present at birth. Here we review the current knowledge on the role of the SLC4A11 gene, protein, and its mutations in the pathophysiology and clinical presentation of CHED. Individuals with CHED have mutations in SLC4A11 which encodes a transmembrane protein in the SLC4 family of bicarbonate transporters. The expression of SLC4A11 in the corneal endothelium and inner ear patterns the deficits seen in CHED with corneal edema and hearing loss (Harboyan syndrome). slc4a11-null-mouse models recapitulate the CHED disease phenotype, thus establishing a functional role for SLC4A11 in CHED. However, the transport function of SLC4A11 remains unsettled. Some of the roles that have been attributed to SLC4A11 include H(+) and NH4 (+) permeation, electrogenic Na(+)-H(+) exchange, and water transport. Future studies of the consequences of SLC4A11 dysfunction as well as further understanding of corneal endothelial ion transport will help clarify the involvement of SLC4A11 in the pathophysiology of CHED.
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Newborn Glaucoma with Imperforate Pupil. Optom Vis Sci 2015; 92:e380-2. [PMID: 26192154 DOI: 10.1097/opx.0000000000000674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
PURPOSE This case report describes the surgical technique of trabeculectomy, mechanical separation of the iris from the cornea, and creation of a pupillary aperture by an automated vitrector in a child with newborn glaucoma with imperforate pupil. CASE REPORT A 1-month-old child was referred to us with the diagnosis of congenital glaucoma of the left eye. Examination under anesthesia revealed megalocornea (corneal diameter, 12 mm) with corneal edema of the left eye whereas the right eye was normal. Intraocular pressure was 8 and 26 mm Hg in the right eye and left eye, respectively. Examination under anesthesia revealed imperforate pupil with uveal tissue attached on the back surface of the left cornea whereas the iris and the pupil of the right eye were normal. A diagnosis of newborn glaucoma and imperforate pupil of the left eye was made and the child underwent trabeculectomy, mechanical separation of the iris from the back surface of the cornea, and creation of pupillary aperture by an automated vitrector. The child had an uneventful postoperative course with disappearance of corneal edema, but there were several linear scars across the cornea. The child completed 3 years of follow-up and his best spectacle corrected visual acuity in the left eye was 20/32 and the intraocular pressure was 10 mm Hg in both eyes. CONCLUSIONS The surgical technique was safe and effective in the restoration of corneal clarity and creation of the pupillary aperture with good visual recovery.
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Zhu YT, Tighe S, Chen SL, John T, Kao WY, Tseng SCG. Engineering of Human Corneal Endothelial Grafts. CURRENT OPHTHALMOLOGY REPORTS 2015; 3:207-217. [PMID: 26509105 DOI: 10.1007/s40135-015-0077-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Human corneal endothelial cells (HCEC) play a pivotal role in maintaining corneal transparency. Unlike in other species, HCEC are notorious for their limited proliferative capacity in vivo after diseases, injury, aging, and surgery. Persistent HCEC dysfunction leads to sight-threatening bullous keratopathy with either an insufficient cell density or retrocorneal membrane due to endothelial-mesenchymal transition (EMT). Presently, the only solution to restore vision in eyes inflicted with bullous keratopathy or retrocorneal membrane relies upon transplantation of a cadaver human donor cornea containing a healthy corneal endothelium. Due to a severe global shortage of donor corneas, in conjunction with an increasing trend toward endothelial keratoplasty, it is opportune to develop a tissue engineering strategy to produce HCEC grafts. Prior attempts of producing these grafts by unlocking the contact inhibition-mediated mitotic block using trypsin-EDTA and culturing of single HCEC in a bFGF-containing medium run the risk of losing the normal phenotype to EMT by activating canonical Wnt signaling and TGF-β signaling. Herein, we summarize our novel approach in engineering HCEC grafts based on selective activation of p120-Kaiso signaling that is coordinated with activation of Rho-ROCK-canonical BMP signaling to reprogram HCEC into neural crest progenitors. Successful commercialization of this engineering technology will not only fulfill the global unmet need but also encourage the scientific community to re-think how cell-cell junctions can be safely perturbed to uncover novel therapeutic potentials in other model systems.
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Affiliation(s)
- Ying-Ting Zhu
- R&D Department, Tissue Tech, Inc., Ocular Surface Center, and Ocular Surface Research & Education Foundation, 7000 SW 97 Ave #212, Miami, FL, 33173, USA
| | - Sean Tighe
- R&D Department, Tissue Tech, Inc., Ocular Surface Center, and Ocular Surface Research & Education Foundation, 7000 SW 97 Ave #212, Miami, FL, 33173, USA
| | - Shuang-Ling Chen
- R&D Department, Tissue Tech, Inc., Ocular Surface Center, and Ocular Surface Research & Education Foundation, 7000 SW 97 Ave #212, Miami, FL, 33173, USA
| | - Thomas John
- Department of Ophthalmology, Loyola University at Chicago, 2160 1 Ave, Maywood, IL 60153, USA
| | - Winston Y Kao
- Department of Ophthalmology, University of Cincinnati, 2600 Clifton Ave, Cincinnati, OH, 45220, USA
| | - Scheffer C G Tseng
- R&D Department, Tissue Tech, Inc., Ocular Surface Center, and Ocular Surface Research & Education Foundation, 7000 SW 97 Ave #212, Miami, FL 33173, USA, Telephone: (305) 274-1299
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Hara S, Hayashi R, Soma T, Kageyama T, Duncan T, Tsujikawa M, Nishida K. Identification and potential application of human corneal endothelial progenitor cells. Stem Cells Dev 2014; 23:2190-201. [PMID: 24588720 DOI: 10.1089/scd.2013.0387] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The corneal endothelium is believed to be developmentally originated from the periocular mesenchyme via the neural crest. Human corneal endothelial progenitor cells (HCEPs) have been investigated because of their potential availability for the tissue regenerative medicine. However, the existence and the properties of HCEPs have not been elucidated yet. We first established a novel serum-free culture system for HCEPs. The HCEPs highly expressed p75 neurotrophin receptor, SOX9, and FOXC2, and partially retained the properties of neural crest and periocular mesenchyme. Further, we demonstrated that HCEPs had a high proliferative potency, and the differentiated HCEP sheets had corneal endothelial function by using the Ussing chamber system and transplantation to the rabbit cornea. These findings suggest that the HCEPs can be selectively expanded from the corneal endothelium using a specific culture system and will provide cell sheets for corneal regenerative medicine.
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Affiliation(s)
- Susumu Hara
- 1 Department of Ophthalmology, Osaka University Graduate School of Medicine , Suita, Japan
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The role of complement activation in the pathogenesis of Fuchs’ dystrophy. Mol Immunol 2014; 58:177-81. [DOI: 10.1016/j.molimm.2013.11.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2013] [Revised: 11/22/2013] [Accepted: 11/23/2013] [Indexed: 11/23/2022]
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Joko T, Suzuki T, Inoue T, Kikuchi M, Hara Y, Shiraishi A, Ohashi Y. Coincidence of Varicella-Zoster Virus Anterior Uveitis in a Patient with Chandler's Syndrome. Case Rep Ophthalmol 2014; 4:274-8. [PMID: 24474927 PMCID: PMC3901595 DOI: 10.1159/000357239] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Purpose We report a patient who, based on the clinical manifestations, was originally diagnosed as having Chandler's syndrome and later developed varicella-zoster virus (VZV) DNA-positive anterior uveitis. Methods The patient with Chandler's syndrome who manifested anterior uveitis underwent a complete ophthalmologic examination. Polymerase chain reaction (PCR) was used to amplify the viral DNA in the aqueous humor to determine the cause of the intraocular inflammation. Results Slit-lamp biomicroscopy showed focal iris atrophy and peripheral anterior synechiae (PAS); specular microscopy of the corneal endothelium disclosed the hammered-silver appearance. Based on these clinical findings, we diagnosed this patient as having Chandler's syndrome. During the follow-up period, however, the inflammatory cells suddenly appeared in the anterior chamber with formation of keratic precipitates and an increased intraocular pressure (IOP). VZV DNA was displayed in the aqueous humor by PCR. Based upon the diagnosis of VZV anterior uveitis, corticosteroids and acyclovir were given topically and systemically. The inflammation subsided with these medications; however, trabeculectomy was finally needed to control the IOP due to PAS progression. Conclusion The coincidence of VZV anterior uveitis with Chandler's syndrome may constitute an implication for the possible viral etiology of iridocorneal endothelial syndrome.
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Affiliation(s)
- Takeshi Joko
- Department of Ophthalmology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Takashi Suzuki
- Department of Ophthalmology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Tomoyuki Inoue
- Department of Ophthalmology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Masaaki Kikuchi
- Department of Ophthalmology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Yuko Hara
- Department of Ophthalmology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Atsushi Shiraishi
- Department of Ophthalmology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Yuichi Ohashi
- Department of Ophthalmology, Ehime University Graduate School of Medicine, Toon, Japan
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Prokudin I, Simons C, Grigg JR, Storen R, Kumar V, Phua ZY, Smith J, Flaherty M, Davila S, Jamieson RV. Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1. Eur J Hum Genet 2013; 22:907-15. [PMID: 24281366 DOI: 10.1038/ejhg.2013.268] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Revised: 10/18/2013] [Accepted: 10/25/2013] [Indexed: 12/13/2022] Open
Abstract
Developmental eye diseases, including cataract/microcornea, Peters anomaly and coloboma/microphthalmia/anophthalmia, are caused by mutations encoding many different signalling and structural proteins in the developing eye. All modes of Mendelian inheritance occur and many are sporadic cases, so provision of accurate recurrence risk information for families and affected individuals is highly challenging. Extreme genetic heterogeneity renders testing for all known disease genes clinically unavailable with traditional methods. We used whole-exome sequencing in 11 unrelated developmental eye disease patients, as it provides a strategy for assessment of multiple disease genes simultaneously. We identified five causative variants in four patients in four different disease genes, GJA8, CRYGC, PAX6 and CYP1B1. This detection rate (36%) is high for a group of patients where clinical testing is frequently not undertaken due to lack of availability and cost. The results affected clinical management in all cases. These variants were detected in the cataract/microcornea and Peters anomaly patients. In two patients with coloboma/microphthalmia, variants in ABCB6 and GDF3 were identified with incomplete penetrance, highlighting the complex inheritance pattern associated with this phenotype. In the coloboma/microphthalmia patients, four other variants were identified in CYP1B1, and CYP1B1 emerged as a candidate gene to be considered as a modifier in coloboma/microphthalmia.
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Affiliation(s)
- Ivan Prokudin
- 1] Eye and Developmental Genetics Research Group, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia [2] Children's Medical Research Institute, Sydney, NSW, Australia
| | - Cas Simons
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
| | - John R Grigg
- 1] Eye and Developmental Genetics Research Group, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia [2] Discipline of Ophthalmology and Save Sight Institute, University of Sydney, Sydney, NSW, Australia
| | - Rebecca Storen
- 1] Eye and Developmental Genetics Research Group, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia [2] Children's Medical Research Institute, Sydney, NSW, Australia [3] Discipline of Ophthalmology and Save Sight Institute, University of Sydney, Sydney, NSW, Australia
| | - Vikrant Kumar
- Human Genetics, Genome Institute of Singapore, Singapore
| | - Zai Y Phua
- Human Genetics, Genome Institute of Singapore, Singapore
| | - James Smith
- Department of Ophthalmology, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Maree Flaherty
- Department of Ophthalmology, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Sonia Davila
- Human Genetics, Genome Institute of Singapore, Singapore
| | - Robyn V Jamieson
- 1] Eye and Developmental Genetics Research Group, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia [2] Children's Medical Research Institute, Sydney, NSW, Australia [3] Discipline of Ophthalmology and Save Sight Institute, University of Sydney, Sydney, NSW, Australia [4] Disciplines of Paediatrics and Child Health and Genetic Medicine, University of Sydney, Sydney, NSW, Australia
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Mimura T, Yamagami S, Amano S. Corneal endothelial regeneration and tissue engineering. Prog Retin Eye Res 2013; 35:1-17. [PMID: 23353595 DOI: 10.1016/j.preteyeres.2013.01.003] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Revised: 01/05/2013] [Accepted: 01/08/2013] [Indexed: 02/07/2023]
Abstract
Human corneal endothelial cells (HCECs) have a limited proliferative capacity. Descemet stripping with automated endothelial keratoplasty (DSAEK) has become the preferred method for the treatment of corneal endothelial deficiency, but it requires a donor cornea. To overcome the shortage of donor corneas, transplantation of cultured HCEC sheets has been attempted in experimental studies. This review summarizes current knowledge about the mechanisms of corneal endothelial wound healing and about tissue engineering for the corneal endothelium. We also discuss recent work on tissue engineering for DSAEK grafts using cultured HCECs and HCEC precursor cell isolation method (the sphere-forming assay). DSAEK grafts (HCEC sheets) were constructed by seeding cultured HCECs on human amniotic membrane, thin human corneal stroma, and collagen sheets. The pump function of the HCEC sheets thus obtained was approximately 75%-95% of that for human donor corneas. HCEC sheets were transplanted onto rabbit corneas after DSAEK. While the untransplanted control group displayed severe stromal edema, the transplanted group had clear corneas throughout the observation period. The sphere-forming assay using donor human corneal endothelium or cultured HCECs can achieved mass production of human corneal endothelial precursors. These findings indicate that cultured HCECs transplanted after DSAEK can perform effective corneal dehydration in vivo and suggest the feasibility of employing the transplantation of cultured HCECs to treat endothelial dysfunction. Additionally, corneal endothelial precursors may be an effective strategy for corneal endothelial regeneration.
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Affiliation(s)
- Tatsuya Mimura
- Department of Ophthalmology, Tokyo Women's Medical University Medical Center East, 2-1-10 Nishiogu, Arakawa-ku, Tokyo 116-8567, Japan.
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Hamoudi H, Rudnick JC, Prause JU, Tauscher K, Breithaupt A, Teifke JP, Heegaard S. Anterior segment dysgenesis (Peters' anomaly) in two snow leopard (Panthera uncia) cubs. Vet Ophthalmol 2012; 16 Suppl 1:130-4. [DOI: 10.1111/vop.12017] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Hassan Hamoudi
- Department of Ophthalmology; University of Copenhagen, Glostrup Hospital; Glostrup Denmark
| | | | - Jan U. Prause
- Department of Neuroscience and Pharmacology, Eye Pathology Institute; University of Copenhagen; Copenhagen Denmark
| | - Kerstin Tauscher
- Friedrich-Löffler-Institut; Bundesforschungsinstitut fuer Tiergesundheit; Greifswald Germany
| | - Angele Breithaupt
- Friedrich-Löffler-Institut; Bundesforschungsinstitut fuer Tiergesundheit; Greifswald Germany
| | - Jens P. Teifke
- Friedrich-Löffler-Institut; Bundesforschungsinstitut fuer Tiergesundheit; Greifswald Germany
| | - Steffen Heegaard
- Department of Ophthalmology; University of Copenhagen, Glostrup Hospital; Glostrup Denmark
- Department of Neuroscience and Pharmacology, Eye Pathology Institute; University of Copenhagen; Copenhagen Denmark
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50
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Robert AM, Renard G, Robert L, Bourges JL. [The irido-corneo-endothelial syndrome. The loss of the control of corneal endothelial cell cycle. A review]. ACTA ACUST UNITED AC 2012; 61:75-82. [PMID: 23123109 DOI: 10.1016/j.patbio.2012.09.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Accepted: 09/05/2012] [Indexed: 12/13/2022]
Abstract
The three major symptoms of the irido-corneo-endothelial syndrome are the alterations of the corneal endothelium and of the iris with a loss of the regulation of the cell cycle, and the progressive obstruction of the irido-corneal angle. This rare pathology attacks mainly young adult women. Most of the symptoms and complications originate from the excessive proliferation of the corneal endothelial cells accompanied by the evolution of their phenotype towards that of the epithelial cells. In normal conditions the corneal endothelial cells do not divide, they are blocked in the G1 stage of the cell cycle, mainly because of the action of the inhibitors of cyclin-dependent kinases. Still these cells retain a good capacity for proliferation, which can be induced by the down-regulation of the expression of the inhibitors of the cyclin-dependent kinases. This proliferative capacity declines with age and is also different according to the localization of the cells: it is more intense with those originating from the central area then in those from the peripheral area of the cornea. The age-related decline of the proliferative capacity is not due to the shortening of the telomers, but to the stress-induced accelerated senescence of the cells.
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Affiliation(s)
- A M Robert
- Laboratoire de recherche ophtalmologique, université Sorbonne Paris Cité, faculté de médecine Paris Descartes, hôpital Hôtel-Dieu, 1, place du Parvis-Notre-Dame, 75004 Paris, France
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