|
1
|
Zhang C, Lin Z, Yu Y, Wu S, Huang H, Huang Y, Liu J, Mo K, Tan J, Han Z, Li M, Zhao W, Ouyang H, Chen X, Wang L. Deciphering the dynamic single-cell transcriptional landscape in the ocular surface ectoderm differentiation system. LIFE MEDICINE 2024; 3:lnae033. [PMID: 39872440 PMCID: PMC11749776 DOI: 10.1093/lifemedi/lnae033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 09/04/2024] [Indexed: 01/30/2025]
Abstract
The ocular surface ectoderm (OSE) is essential for the development of the ocular surface, yet the molecular mechanisms driving its differentiation are not fully understood. In this study, we used single-cell transcriptomic analysis to explore the dynamic cellular trajectories and regulatory networks during the in vitro differentiation of embryonic stem cells (ESCs) into the OSE lineage. We identified nine distinct cell subpopulations undergoing differentiation along three main developmental branches: neural crest, neuroectodermal, and surface ectodermal lineages. Key marker gene expression, transcription factor activity, and signaling pathway insights revealed stepwise transitions from undifferentiated ESCs to fate-specified cell types, including a PAX6 + TP63 + population indicative of OSE precursors. Comparative analysis with mouse embryonic development confirmed the model's accuracy in mimicking in vivo epiblast-to-surface ectoderm dynamics. By integrating temporal dynamics of transcription factor activation and cell-cell communication, we constructed a comprehensive molecular atlas of the differentiation pathway from ESCs to distinct ectodermal lineages. This study provides new insights into the cellular heterogeneity and regulatory mechanisms of OSE development, aiding the understanding of ocular surface biology and the design of cell-based therapies for ocular surface disorders.
Collapse
Affiliation(s)
- Canwei Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou 510060, China
- Department of Ophthalmology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
| | - Zesong Lin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou 510060, China
| | - Yankun Yu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou 510060, China
- Department of Pathology, The First Affiliated Hospital of Shihezi University, Shihezi 832002, China
| | - Siqi Wu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou 510060, China
| | - Huaxing Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou 510060, China
| | - Ying Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou 510060, China
| | - Jiafeng Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou 510060, China
| | - Kunlun Mo
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou 510060, China
| | - Jieying Tan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou 510060, China
| | - Zhuo Han
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou 510060, China
| | - Mingsen Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou 510060, China
| | - Wei Zhao
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Hong Ouyang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou 510060, China
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Xiangjun Chen
- Eye Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310020, China
| | - Li Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou 510060, China
| |
Collapse
|
|
2
|
Li M, Sun H, Hou Z, Hao S, Jin L, Wang B. Engineering the Physical Microenvironment into Neural Organoids for Neurogenesis and Neurodevelopment. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2306451. [PMID: 37771182 DOI: 10.1002/smll.202306451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 09/04/2023] [Indexed: 09/30/2023]
Abstract
Understanding the signals from the physical microenvironment is critical for deciphering the processes of neurogenesis and neurodevelopment. The discovery of how surrounding physical signals shape human developing neurons is hindered by the bottleneck of conventional cell culture and animal models. Notwithstanding neural organoids provide a promising platform for recapitulating human neurogenesis and neurodevelopment, building neuronal physical microenvironment that accurately mimics the native neurophysical features is largely ignored in current organoid technologies. Here, it is discussed how the physical microenvironment modulates critical events during the periods of neurogenesis and neurodevelopment, such as neural stem cell fates, neural tube closure, neuronal migration, axonal guidance, optic cup formation, and cortical folding. Although animal models are widely used to investigate the impacts of physical factors on neurodevelopment and neuropathy, the important roles of human stem cell-derived neural organoids in this field are particularly highlighted. Considering the great promise of human organoids, building neural organoid microenvironments with mechanical forces, electrophysiological microsystems, and light manipulation will help to fully understand the physical cues in neurodevelopmental processes. Neural organoids combined with cutting-edge techniques, such as advanced atomic force microscopes, microrobots, and structural color biomaterials might promote the development of neural organoid-based research and neuroscience.
Collapse
Affiliation(s)
- Minghui Li
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Heng Sun
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
| | - Zongkun Hou
- Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, Engineering Research Center of Cellular Immunotherapy of Guizhou Province, School of Biology and Engineering/School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550025, China
| | - Shilei Hao
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
| | - Liang Jin
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
| | - Bochu Wang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
| |
Collapse
|
|
3
|
Gupta S, Lytvynchuk L, Ardan T, Studenovska H, Faura G, Eide L, Znaor L, Erceg S, Stieger K, Motlik J, Bharti K, Petrovski G. Retinal Pigment Epithelium Cell Development: Extrapolating Basic Biology to Stem Cell Research. Biomedicines 2023; 11:310. [PMID: 36830851 PMCID: PMC9952929 DOI: 10.3390/biomedicines11020310] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 01/13/2023] [Accepted: 01/17/2023] [Indexed: 01/24/2023] Open
Abstract
The retinal pigment epithelium (RPE) forms an important cellular monolayer, which contributes to the normal physiology of the eye. Damage to the RPE leads to the development of degenerative diseases, such as age-related macular degeneration (AMD). Apart from acting as a physical barrier between the retina and choroidal blood vessels, the RPE is crucial in maintaining photoreceptor (PR) and visual functions. Current clinical intervention to treat early stages of AMD includes stem cell-derived RPE transplantation, which is still in its early stages of evolution. Therefore, it becomes essential to derive RPEs which are functional and exhibit features as observed in native human RPE cells. The conventional strategy is to use the knowledge obtained from developmental studies using various animal models and stem cell-based exploratory studies to understand RPE biogenies and developmental trajectory. This article emphasises such studies and aims to present a comprehensive understanding of the basic biology, including the genetics and molecular pathways of RPE development. It encompasses basic developmental biology and stem cell-based developmental studies to uncover RPE differentiation. Knowledge of the in utero developmental cues provides an inclusive methodology required for deriving RPEs using stem cells.
Collapse
Affiliation(s)
- Santosh Gupta
- Center for Eye Research and Innovative Diagnostics, Department of Ophthalmology, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway
| | - Lyubomyr Lytvynchuk
- Department of Ophthalmology, Justus Liebig University Giessen, University Hospital Giessen and Marburg GmbH, 35392 Giessen, Germany
- Karl Landsteiner Institute for Retinal Research and Imaging, 1030 Vienna, Austria
| | - Taras Ardan
- Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, 27721 Libechov, Czech Republic
| | - Hana Studenovska
- Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, 16206 Prague, Czech Republic
| | - Georgina Faura
- Department of Medical Biochemistry, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway
| | - Lars Eide
- Department of Medical Biochemistry, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway
| | - Ljubo Znaor
- Department of Ophthalmology, University of Split School of Medicine and University Hospital Centre, 21000 Split, Croatia
| | - Slaven Erceg
- Research Center “Principe Felipe”, Stem Cell Therapies in Neurodegenerative Diseases Laboratory, 46012 Valencia, Spain
- Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 11720 Prague, Czech Republic
| | - Knut Stieger
- Department of Ophthalmology, Justus Liebig University Giessen, University Hospital Giessen and Marburg GmbH, 35392 Giessen, Germany
| | - Jan Motlik
- Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, 27721 Libechov, Czech Republic
| | - Kapil Bharti
- Ocular and Stem Cell Translational Research Section, NEI, NIH, Bethesda, MD 20892, USA
| | - Goran Petrovski
- Center for Eye Research and Innovative Diagnostics, Department of Ophthalmology, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway
- Department of Ophthalmology, University of Split School of Medicine and University Hospital Centre, 21000 Split, Croatia
- Department of Ophthalmology, Oslo University Hospital, 0450 Oslo, Norway
| |
Collapse
|
|
4
|
Li M, Zeng Y, Ge L, Gong J, Weng C, Yang C, Yang J, Fang Y, Li Q, Zou T, Xu H. Evaluation of the influences of low dose polybrominated diphenyl ethers exposure on human early retinal development. ENVIRONMENT INTERNATIONAL 2022; 163:107187. [PMID: 35313214 DOI: 10.1016/j.envint.2022.107187] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 01/17/2022] [Accepted: 03/14/2022] [Indexed: 06/14/2023]
Abstract
Increasing evidence in animal models has suggested that polybrominated diphenyl ethers (PBDEs), a class of brominated flame retardants, can cause retinotoxicity. However, data on the influence of PBDE treatment on human retinal development are scarce due to the lack of appropriate models. In the present study, we report the utilization of human embryonic stem cell-derived retinal organoids (hESC-ROs) for toxicity assessment of the most common PBDE congener (BDE-47) during the early stages of retinal development. Exposure to BDE-47 decreased the thickness and area of the neural retina (NR) of hESC-ROs in a dose- and time-dependent manner. Abnormal retinal cell distributions, disordered NR structures, and neural rosette-like structures were found on hESC-ROs after low-level BDE-47 exposure. Moreover, BDE-47 exposure decreased cell proliferation, promoted cell apoptosis, and caused abnormal differentiation. Transcriptomic analysis demonstrated that differentially expressed genes, caused by BDE-47, were enriched in extracellular matrix organization. Metabolomic studies of hESC-ROs revealed significant changes in the metabolism of purine and glutathione after BDE-47 exposure for five weeks. This study clarifies the retinotoxicity of low-level BDE-47 treatment and highlights the powerfulness of the hESC-RO model, deepening our understanding of BDE-47-driven human early retina developmental toxicity.
Collapse
Affiliation(s)
- Minghui Li
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China
| | - Yuxiao Zeng
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China
| | - Lingling Ge
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China
| | - Jing Gong
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Chuanhuang Weng
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China
| | - Cao Yang
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China
| | - Junling Yang
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China
| | - Yajie Fang
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China
| | - Qiyou Li
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China
| | - Ting Zou
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China
| | - Haiwei Xu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China.
| |
Collapse
|
|
5
|
German OL, Vallese-Maurizi H, Soto TB, Rotstein NP, Politi LE. Retina stem cells, hopes and obstacles. World J Stem Cells 2021; 13:1446-1479. [PMID: 34786153 PMCID: PMC8567457 DOI: 10.4252/wjsc.v13.i10.1446] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/14/2021] [Accepted: 09/17/2021] [Indexed: 02/07/2023] Open
Abstract
Retinal degeneration is a major contributor to visual dysfunction worldwide. Although it comprises several eye diseases, loss of retinal pigment epithelial (RPE) and photoreceptor cells are the major contributors to their pathogenesis. Early therapies included diverse treatments, such as provision of anti-vascular endothelial growth factor and many survival and trophic factors that, in some cases, slow down the progression of the degeneration, but do not effectively prevent it. The finding of stem cells (SC) in the eye has led to the proposal of cell replacement strategies for retina degeneration. Therapies using different types of SC, such as retinal progenitor cells (RPCs), embryonic SC, pluripotent SCs (PSCs), induced PSCs (iPSCs), and mesenchymal stromal cells, capable of self-renewal and of differentiating into multiple cell types, have gained ample support. Numerous preclinical studies have assessed transplantation of SC in animal models, with encouraging results. The aim of this work is to revise the different preclinical and clinical approaches, analyzing the SC type used, their efficacy, safety, cell attachment and integration, absence of tumor formation and immunorejection, in order to establish which were the most relevant and successful. In addition, we examine the questions and concerns still open in the field. The data demonstrate the existence of two main approaches, aimed at replacing either RPE cells or photoreceptors. Emerging evidence suggests that RPCs and iPSC are the best candidates, presenting no ethical concerns and a low risk of immunorejection. Clinical trials have already supported the safety and efficacy of SC treatments. Serious concerns are pending, such as the risk of tumor formation, lack of attachment or integration of transplanted cells into host retinas, immunorejection, cell death, and also ethical. However, the amazing progress in the field in the last few years makes it possible to envisage safe and effective treatments to restore vision loss in a near future.
Collapse
Affiliation(s)
- Olga L German
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, Bahia blanca 8000, Buenos Aires, Argentina
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Harmonie Vallese-Maurizi
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, Bahia blanca 8000, Buenos Aires, Argentina
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Tamara B Soto
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Nora P Rotstein
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, Bahia blanca 8000, Buenos Aires, Argentina
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Luis Enrique Politi
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| |
Collapse
|
|
6
|
Zeng Y, Li M, Zou T, Chen X, Li Q, Li Y, Ge L, Chen S, Xu H. The Impact of Particulate Matter (PM2.5) on Human Retinal Development in hESC-Derived Retinal Organoids. Front Cell Dev Biol 2021; 9:607341. [PMID: 33644046 PMCID: PMC7907455 DOI: 10.3389/fcell.2021.607341] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 01/04/2021] [Indexed: 12/21/2022] Open
Abstract
Increasing evidence demonstrated that PM2.5 could cross the placenta and fetal blood-brain barrier, causing neurotoxicity of embryonic development. The retina, an embryologic extension of the central nervous system, is extremely sensitive and vulnerable to environmental insults. The adverse effects of PM2.5 exposure on the retina during embryonic neurodevelopment are still largely unknown. Our goal was to investigate the effect of PM2.5 on human retinal development, which was recapitulated by human embryonic stem cell (hESC)-derived retinal organoids (hEROs). In the present study, using the hEROs as the model, the influences and the mechanisms of PM2.5 on the developing retina were analyzed. It demonstrated that the formation rate of the hERO-derived neural retina (NR) was affected by PM2.5 in a concentration dosage-dependent manner. The areas of hEROs and the thickness of hERO-NRs were significantly reduced after PM2.5 exposure at the concentration of 25, 50, and 100 μg/ml, which was due to the decrease of proliferation and the increase of apoptosis. Although we did not spot significant effects on retinal differentiation, PM2.5 exposure did lead to hERO-NR cell disarranging and structural disorder, especially retinal ganglion cell dislocation. Transcriptome analysis showed that PM2.5 treatment was significantly associated with the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways and reduced the level of the fibroblast growth factors (FGFs), particularly FGF8 and FGF10. These results provided evidence that PM2.5 exposure potentially inhibited proliferation and increased apoptosis at the early development stage of the human NR, probably through the MAPK and PI3K/Akt pathway. Our study suggested that exposure to PM2.5 suppressed cell proliferation and promoted cell apoptosis, thereby contributing to abnormal human retinal development.
Collapse
Affiliation(s)
- Yuxiao Zeng
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Minghui Li
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Ting Zou
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Xi Chen
- Department of Ophthalmology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Qiyou Li
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Yijian Li
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Lingling Ge
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Siyu Chen
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Haiwei Xu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| |
Collapse
|
|
7
|
Li M, Yang T, Gao L, Xu H. An inadvertent issue of human retina exposure to endocrine disrupting chemicals: A safety assessment. CHEMOSPHERE 2021; 264:128484. [PMID: 33022499 DOI: 10.1016/j.chemosphere.2020.128484] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/07/2020] [Accepted: 09/27/2020] [Indexed: 06/11/2023]
Abstract
Endocrine disrupting chemicals (EDCs) are a group of chemical compounds that present a considerable public health problem due to their pervasiveness and associations with chronic diseases. EDCs can interrupt the endocrine system and interfere with hormone homeostasis, leading to abnormalities in human physiology. Much attention has been focused on the adverse effects EDCs have on the reproductive system, neurogenesis, neuroendocrine system, and thyroid dysfunction. The eye is usually directly exposed to the surrounding environment; however, the influences of EDCs on the eye have received comparatively little attention. Ocular diseases, such as ocular surface diseases and retinal diseases, have been implicated in hormone deficiency or excess. Epidemiologic studies have shown that EDC exposure not only causes ocular surface disorders, such as dry eye, but also associates with visual deficits and retinopathy. EDCs can pass through the human blood-retinal barrier and enter the neural retina, and can then accumulate in the retina. The retina is an embryologic extension of the central nervous system, and is extremely sensitive and vulnerable to EDCs that could be passed across the placenta during critical periods of retinal development. Subtle alterations in the retinal development process usually result in profound immediate, long-term, and delayed effects late in life. This review, based on extensive literature survey, briefly summarizes the current knowledge about the impact of representative manufactured EDCs on retinal toxicity, including retinal structure alterations and dysfunction. We also highlight the potential mechanism of action of EDCs on the retina, and the predictive retinal models of EDC exposure.
Collapse
Affiliation(s)
- Minghui Li
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Tian Yang
- Department of Cold Environmental Medicine, College of High Altitude Military Medicine, Third Military Medical University (Army Medical University), Chongqing, China
| | - Lixiong Gao
- Department of Ophthalmology, Third Medical Center of PLA General Hospital, Beijing, China
| | - Haiwei Xu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China.
| |
Collapse
|
|
8
|
Subramaniam MD, Iyer M, Nair AP, Venkatesan D, Mathavan S, Eruppakotte N, Kizhakkillach S, Chandran MK, Roy A, Gopalakrishnan AV, Vellingiri B. Oxidative stress and mitochondrial transfer: A new dimension towards ocular diseases. Genes Dis 2020; 9:610-637. [PMID: 35782976 PMCID: PMC9243399 DOI: 10.1016/j.gendis.2020.11.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 09/18/2020] [Accepted: 11/27/2020] [Indexed: 12/12/2022] Open
Abstract
Ocular cells like, retinal pigment epithelium (RPE) is a highly specialized pigmented monolayer of post-mitotic cells, which is located in the posterior segment of the eye between neuro sensory retina and vascular choroid. It functions as a selective barrier and nourishes retinal visual cells. As a result of high-level oxygen consumption of retinal cells, RPE cells are vulnerable to chronic oxidative stress and an increased level of reactive oxygen species (ROS) generated from mitochondria. These oxidative stress and ROS generation in retinal cells lead to RPE degeneration. Various sources including mtDNA damage could be an important factor of oxidative stress in RPE. Gene therapy and mitochondrial transfer studies are emerging fields in ocular disease research. For retinal degenerative diseases stem cell-based transplantation methods are developed from basic research to preclinical and clinical trials. Translational research contributions of gene and cell therapy would be a new strategy to prevent, treat and cure various ocular diseases. This review focuses on the effect of oxidative stress in ocular cell degeneration and recent translational researches on retinal degenerative diseases to cure blindness.
Collapse
Affiliation(s)
- Mohana Devi Subramaniam
- SN ONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai 600006, Tamil Nadu, India
- Corresponding author.
| | - Mahalaxmi Iyer
- SN ONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai 600006, Tamil Nadu, India
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore 641 043, Tamil Nadu, India
| | - Aswathy P. Nair
- SN ONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai 600006, Tamil Nadu, India
| | - Dhivya Venkatesan
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
| | - Sinnakaruppan Mathavan
- SN ONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai 600006, Tamil Nadu, India
| | - Nimmisha Eruppakotte
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
| | - Soumya Kizhakkillach
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
| | - Manoj kumar Chandran
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
| | - Ayan Roy
- Department of Biotechnology, Lovely Professional University, Punjab 144411, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Bio Sciences and Technology (SBST), Vellore Institute of Technology (VIT), Vellore 600127, India
| | - Balachandar Vellingiri
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
- Corresponding author. Human Molecular Cytogenetics and Stem Cell, Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India.Fax: +91 422 2422387.
| |
Collapse
|
|
9
|
Zhou J, Benito-Martin A, Mighty J, Chang L, Ghoroghi S, Wu H, Wong M, Guariglia S, Baranov P, Young M, Gharbaran R, Emerson M, Mark MT, Molina H, Canto-Soler MV, Selgas HP, Redenti S. Retinal progenitor cells release extracellular vesicles containing developmental transcription factors, microRNA and membrane proteins. Sci Rep 2018; 8:2823. [PMID: 29434302 PMCID: PMC5809580 DOI: 10.1038/s41598-018-20421-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 01/15/2018] [Indexed: 12/27/2022] Open
Abstract
A range of cell types, including embryonic stem cells, neurons and astrocytes have been shown to release extracellular vesicles (EVs) containing molecular cargo. Across cell types, EVs facilitate transfer of mRNA, microRNA and proteins between cells. Here we describe the release kinetics and content of EVs from mouse retinal progenitor cells (mRPCs). Interestingly, mRPC derived EVs contain mRNA, miRNA and proteins associated with multipotency and retinal development. Transcripts enclosed in mRPC EVs, include the transcription factors Pax6, Hes1, and Sox2, a mitotic chromosome stabilizer Ki67, and the neural intermediate filaments Nestin and GFAP. Proteomic analysis of EV content revealed retinogenic growth factors and morphogen proteins. mRPC EVs were shown to transfer GFP mRNA between cell populations. Finally, analysis of EV mediated functional cargo delivery, using the Cre-loxP recombination system, revealed transfer and uptake of Cre+ EVs, which were then internalized by target mRPCs activating responder loxP GFP expression. In summary, the data supports a paradigm of EV genetic material encapsulation and transfer within RPC populations. RPC EV transfer may influence recipient RPC transcriptional and post-transcriptional regulation, representing a novel mechanism of differentiation and fate determination during retinal development.
Collapse
Affiliation(s)
- Jing Zhou
- Department of Biological Sciences, Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY, 10468, USA.,Biology Doctoral Program, The Graduate School and University Center, City University of New York, 365 5th Avenue, New York, NY, 10016, USA
| | - Alberto Benito-Martin
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medical College, New York, New York, 10021, USA
| | - Jason Mighty
- Department of Biological Sciences, Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY, 10468, USA.,Biology Doctoral Program, The Graduate School and University Center, City University of New York, 365 5th Avenue, New York, NY, 10016, USA
| | - Lynne Chang
- Nikon Instruments Inc, 1300 Walt Whitman Road, Melville, NY, 11747, USA
| | - Shima Ghoroghi
- Department of Biological Sciences, Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY, 10468, USA
| | - Hao Wu
- Department of Biological Sciences, Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY, 10468, USA.,Biology Doctoral Program, The Graduate School and University Center, City University of New York, 365 5th Avenue, New York, NY, 10016, USA
| | - Madeline Wong
- Department of Biological Sciences, Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY, 10468, USA
| | - Sara Guariglia
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 722 West 168th St, New York, NY, 10032, USA
| | - Petr Baranov
- The Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA, 02114, USA
| | - Michael Young
- The Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA, 02114, USA
| | - Rajendra Gharbaran
- Department of Biological Sciences, Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY, 10468, USA
| | - Mark Emerson
- Biology Doctoral Program, The Graduate School and University Center, City University of New York, 365 5th Avenue, New York, NY, 10016, USA.,Department of Biology, The City College of New York, City University of New York, New York, NY, 10031, USA
| | - Milica Tesic Mark
- Proteomics Resource Center, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA
| | - Henrik Molina
- Proteomics Resource Center, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA
| | - M Valeria Canto-Soler
- The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Hector Peinado Selgas
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medical College, New York, New York, 10021, USA.,Microenvironment and Metastasis Laboratory, Department of Molecular Oncology, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, Madrid, E28029, Spain
| | - Stephen Redenti
- Department of Biological Sciences, Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY, 10468, USA. .,Biology Doctoral Program, The Graduate School and University Center, City University of New York, 365 5th Avenue, New York, NY, 10016, USA. .,Biochemistry Doctoral Program, The Graduate School and University Center, City University of New York, 365 5th Avenue, New York, NY, 10016, USA.
| |
Collapse
|
|
10
|
Gao L, Chen X, Zeng Y, Li Q, Zou T, Chen S, Wu Q, Fu C, Xu H, Yin ZQ. Intermittent high oxygen influences the formation of neural retinal tissue from human embryonic stem cells. Sci Rep 2016; 6:29944. [PMID: 27435522 PMCID: PMC4951725 DOI: 10.1038/srep29944] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 06/24/2016] [Indexed: 12/26/2022] Open
Abstract
The vertebrate retina is a highly multilayered nervous tissue with a large diversity of cellular components. With the development of stem cell technologies, human retinas can be generated in three-dimensional (3-D) culture in vitro. However, understanding the factors modulating key productive processes and the way that they influence development are far from clear. Oxygen, as the most essential element participating in metabolism, is a critical factor regulating organic development. In this study, using 3-D culture of human stem cells, we examined the effect of intermittent high oxygen treatment (40% O2) on the formation and cellular behavior of neural retinas (NR) in the embryonic body (EB). The volume of EB and number of proliferating cells increased significantly under 40% O2 on day 38, 50, and 62. Additionally, the ratio of PAX6+ cells within NR was significantly increased. The neural rosettes could only develop with correct apical-basal polarity under 40% O2. In addition, the generation, migration and maturation of retinal ganglion cells were enhanced under 40% O2. All of these results illustrated that 40% O2 strengthened the formation of NR in EB with characteristics similar to the in vivo state, suggesting that the hyperoxic state facilitated the retinal development in vitro.
Collapse
Affiliation(s)
- Lixiong Gao
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China.,Key Lab of Visual Damage and Regeneration &Restoration of Chongqing, Chongqing 400038, China
| | - Xi Chen
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China.,Key Lab of Visual Damage and Regeneration &Restoration of Chongqing, Chongqing 400038, China.,School of Medicine, Nankai University, Tianjin 300071, China.,Department of Ophthalmology, Chinese People's Liberation Army General Hospital, Beijing 100853, China
| | - Yuxiao Zeng
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China.,Key Lab of Visual Damage and Regeneration &Restoration of Chongqing, Chongqing 400038, China
| | - Qiyou Li
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China.,Key Lab of Visual Damage and Regeneration &Restoration of Chongqing, Chongqing 400038, China
| | - Ting Zou
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China.,Key Lab of Visual Damage and Regeneration &Restoration of Chongqing, Chongqing 400038, China
| | - Siyu Chen
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China.,Key Lab of Visual Damage and Regeneration &Restoration of Chongqing, Chongqing 400038, China
| | - Qian Wu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China.,Key Lab of Visual Damage and Regeneration &Restoration of Chongqing, Chongqing 400038, China
| | - Caiyun Fu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China.,Key Lab of Visual Damage and Regeneration &Restoration of Chongqing, Chongqing 400038, China
| | - Haiwei Xu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China.,Key Lab of Visual Damage and Regeneration &Restoration of Chongqing, Chongqing 400038, China
| | - Zheng Qin Yin
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China.,Key Lab of Visual Damage and Regeneration &Restoration of Chongqing, Chongqing 400038, China
| |
Collapse
|
|
11
|
Conti C, Montero-Fernandez A, Borg E, Osadolor T, Viola P, De Lauretis A, Stock CJ, Bonifazi M, Bonini M, Caramori G, Lindahl G, Blasi FB, Nicholson AG, Wells AU, Sestini P, Renzoni E. Mucins MUC5B and MUC5AC in Distal Airways and Honeycomb Spaces: Comparison among Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia, Fibrotic Nonspecific Interstitial Pneumonitis, and Control Lungs. Am J Respir Crit Care Med 2016; 193:462-4. [PMID: 26871672 DOI: 10.1164/rccm.201507-1322le] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Caterina Conti
- 1 Imperial College London London, United Kingdom and.,2 Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Ca'Granda Ospedale Maggiore Policlinico Milan, Italy
| | | | - Elaine Borg
- 4 University College London Hospital London, United Kingdom
| | - Tina Osadolor
- 3 Royal Brompton and Harefield NHS Foundation Trust London, United Kingdom
| | - Patrizia Viola
- 3 Royal Brompton and Harefield NHS Foundation Trust London, United Kingdom
| | | | | | | | - Matteo Bonini
- 1 Imperial College London London, United Kingdom and
| | | | | | - Francesco B Blasi
- 2 Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Ca'Granda Ospedale Maggiore Policlinico Milan, Italy
| | - Andrew G Nicholson
- 3 Royal Brompton and Harefield NHS Foundation Trust London, United Kingdom
| | - Athol U Wells
- 1 Imperial College London London, United Kingdom and
| | | | | |
Collapse
|
|
12
|
Ouyang H, Goldberg JL, Chen S, Li W, Xu GT, Li W, Zhang K, Nussenblatt RB, Liu Y, Xie T, Chan CC, Zack DJ. Ocular Stem Cell Research from Basic Science to Clinical Application: A Report from Zhongshan Ophthalmic Center Ocular Stem Cell Symposium. Int J Mol Sci 2016; 17:415. [PMID: 27102165 PMCID: PMC4813266 DOI: 10.3390/ijms17030415] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Revised: 03/17/2016] [Accepted: 03/17/2016] [Indexed: 12/16/2022] Open
Abstract
Stem cells hold promise for treating a wide variety of diseases, including degenerative disorders of the eye. The eye is an ideal organ for stem cell therapy because of its relative immunological privilege, surgical accessibility, and its being a self-contained system. The eye also has many potential target diseases amenable to stem cell-based treatment, such as corneal limbal stem cell deficiency, glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa (RP). Among them, AMD and glaucoma are the two most common diseases, affecting over 200 million people worldwide. Recent results on the clinical trial of retinal pigment epithelial (RPE) cells from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) in treating dry AMD and Stargardt’s disease in the US, Japan, England, and China have generated great excitement and hope. This marks the beginning of the ocular stem cell therapy era. The recent Zhongshan Ophthalmic Center Ocular Stem Cell Symposium discussed the potential applications of various stem cell types in stem cell-based therapies, drug discoveries and tissue engineering for treating ocular diseases.
Collapse
Affiliation(s)
- Hong Ouyang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
| | - Jeffrey L Goldberg
- Department of Ophthalmology, Stanford University, Palo Alto, CA 94303, USA.
| | - Shuyi Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
| | - Wei Li
- Unit on Retinal Neurophysiology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Guo-Tong Xu
- Department of Ophthalmology, Tongji University, Shanghai 200092, China.
| | - Wei Li
- Department of Ophthalmology, Xiamen University, Xiamen 361005, China.
| | - Kang Zhang
- Department of Ophthalmology, University of California San Diego, San Diego, CA 92093, USA.
| | - Robert B Nussenblatt
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Yizhi Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
| | - Ting Xie
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
| | - Chi-Chao Chan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Donald J Zack
- Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, MD 21231, USA.
| |
Collapse
|
|
13
|
Stem cell based therapies for age-related macular degeneration: The promises and the challenges. Prog Retin Eye Res 2015; 48:1-39. [PMID: 26113213 DOI: 10.1016/j.preteyeres.2015.06.004] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Revised: 06/05/2015] [Accepted: 06/11/2015] [Indexed: 12/21/2022]
|
|
14
|
A meta-analysis examining the association between the MUC5B rs35705950 T/G polymorphism and susceptibility to idiopathic pulmonary fibrosis. Inflamm Res 2015; 64:463-70. [PMID: 25926289 DOI: 10.1007/s00011-015-0829-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 04/01/2015] [Accepted: 04/23/2015] [Indexed: 01/06/2023] Open
Abstract
OBJECTIVE To explore whether the mucin (MUC) 5B rs35705950 T/G polymorphism confers susceptibility to idiopathic pulmonary fibrosis (IPF). METHODS A meta-analysis was conducted to determine associations between the MUC5B rs35705950 T/G polymorphism and either IPF or connective tissue disease-associated interstitial lung disease (CTD-ILD). We used the allele contrast, recessive, dominant, and additive models. A total of 12 IPF studies comprising 2859 patients and 6901 controls and four CTD-ILD studies involving 903 patients and 3306 controls were included in the meta-analysis. RESULTS There was a significant association between the Tallele of the MUC5B rs35705950 polymorphism and IPF in all subjects (OR 3.768, 95 % CI 2.935-4.836, p < 1.0 × 10(-8)). Analysis after stratification by ethnicity indicated that the Tallele was significantly associated with IPF in Europeans and Asians (OR 3.728, 95 % CI 2.858-4.863, p < 1.0 × 10(-8); OR 4.334, 95 % CI 2.186-8.594, p = 2.6 × 10(-6)). However, there was no association between the Tallele and CTD-ILD in all subjects (OR 1.130, 95 % CI 0.937-1.363, p = 0.200), and in Europeans and Asians. Subgroup analysis by CTD type revealed no association between the Tallele and systemic sclerosis-associated ILD (SSc-ILD) and other CTD-ILDs. CONCLUSIONS The MUC5B rs35705950 T/G polymorphism confers susceptibility to IPF in Europeans and Asians, but is not associated with susceptibility to CTD-ILD.
Collapse
|
|
15
|
Luo J, Baranov P, Patel S, Ouyang H, Quach J, Wu F, Qiu A, Luo H, Hicks C, Zeng J, Zhu J, Lu J, Sfeir N, Wen C, Zhang M, Reade V, Patel S, Sinden J, Sun X, Shaw P, Young M, Zhang K. Human retinal progenitor cell transplantation preserves vision. J Biol Chem 2014; 289:6362-6371. [PMID: 24407289 DOI: 10.1074/jbc.m113.513713] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Cell transplantation is a potential therapeutic strategy for retinal degenerative diseases involving the loss of photoreceptors. However, it faces challenges to clinical translation due to safety concerns and a limited supply of cells. Human retinal progenitor cells (hRPCs) from fetal neural retina are expandable in vitro and maintain an undifferentiated state. This study aimed to investigate the therapeutic potential of hRPCs transplanted into a Royal College of Surgeons (RCS) rat model of retinal degeneration. At 12 weeks, optokinetic response showed that hRPC-grafted eyes had significantly superior visual acuity compared with vehicle-treated eyes. Histological evaluation of outer nuclear layer (ONL) characteristics such as ONL thickness, spread distance, and cell count demonstrated a significantly greater preservation of the ONL in hRPC-treated eyes compared with both vehicle-treated and control eyes. The transplanted hRPCs arrested visual decline over time in the RCS rat and rescued retinal morphology, demonstrating their potential as a therapy for retinal diseases. We suggest that the preservation of visual acuity was likely achieved through host photoreceptor rescue. We found that hRPC transplantation into the subretinal space of RCS rats was well tolerated, with no adverse effects such as tumor formation noted at 12 weeks after treatment.
Collapse
Affiliation(s)
- Jing Luo
- Department of Ophthalmology, Second Xiangya Hospital and International Academy of Translational Medicine, Central South University, Changsha, Hunan 410011, China; Institute for Genomic Medicine and Shiley Eye Center, University of California at San Diego, La Jolla, California 92093
| | - Petr Baranov
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, Massachusetts 02114
| | - Sherrina Patel
- Institute for Genomic Medicine and Shiley Eye Center, University of California at San Diego, La Jolla, California 92093
| | - Hong Ouyang
- Institute for Genomic Medicine and Shiley Eye Center, University of California at San Diego, La Jolla, California 92093
| | - John Quach
- Institute for Genomic Medicine and Shiley Eye Center, University of California at San Diego, La Jolla, California 92093
| | - Frances Wu
- Institute for Genomic Medicine and Shiley Eye Center, University of California at San Diego, La Jolla, California 92093
| | - Austin Qiu
- Institute for Genomic Medicine and Shiley Eye Center, University of California at San Diego, La Jolla, California 92093; Molecular Medicine Research Center, West China Hospital, Chengdu, Sichuan 610041, China
| | - Hongrong Luo
- Institute for Genomic Medicine and Shiley Eye Center, University of California at San Diego, La Jolla, California 92093; Molecular Medicine Research Center, West China Hospital, Chengdu, Sichuan 610041, China
| | - Caroline Hicks
- ReNeuron Ltd., Guildford, Surrey GU2 7AF, United Kingdom
| | - Jing Zeng
- Institute for Genomic Medicine and Shiley Eye Center, University of California at San Diego, La Jolla, California 92093; Department of Ophthalmology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Jing Zhu
- Institute for Genomic Medicine and Shiley Eye Center, University of California at San Diego, La Jolla, California 92093; Molecular Medicine Research Center, West China Hospital, Chengdu, Sichuan 610041, China
| | - Jessica Lu
- Institute for Genomic Medicine and Shiley Eye Center, University of California at San Diego, La Jolla, California 92093
| | - Nicole Sfeir
- Institute for Genomic Medicine and Shiley Eye Center, University of California at San Diego, La Jolla, California 92093
| | - Cindy Wen
- Institute for Genomic Medicine and Shiley Eye Center, University of California at San Diego, La Jolla, California 92093
| | - Meixia Zhang
- Molecular Medicine Research Center, West China Hospital, Chengdu, Sichuan 610041, China
| | | | - Sara Patel
- Molecular Medicine Research Center, West China Hospital, Chengdu, Sichuan 610041, China
| | - John Sinden
- Molecular Medicine Research Center, West China Hospital, Chengdu, Sichuan 610041, China
| | - Xiaodong Sun
- Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 200080, China; Eye Research Institute, Shanghai JiaoTong University, Shanghai 200080, China.
| | - Peter Shaw
- Institute for Genomic Medicine and Shiley Eye Center, University of California at San Diego, La Jolla, California 92093
| | - Michael Young
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, Massachusetts 02114
| | - Kang Zhang
- Department of Ophthalmology, Second Xiangya Hospital and International Academy of Translational Medicine, Central South University, Changsha, Hunan 410011, China; Institute for Genomic Medicine and Shiley Eye Center, University of California at San Diego, La Jolla, California 92093; Molecular Medicine Research Center, West China Hospital, Chengdu, Sichuan 610041, China; Veterans Affairs Healthcare System, San Diego, California 92161.
| |
Collapse
|
|
16
|
Ouyang H, Zhuo Y, Zhang K. WNT signaling in stem cell differentiation and tumor formation. J Clin Invest 2013; 123:1422-4. [PMID: 23524963 DOI: 10.1172/jci69324] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Embryonic stem cells (ESCs) hold great therapeutic promise for the regeneration of functional cell types and clinical applications. However, tumorigenic potential of stem cells in a transplanted host remains a major obstacle. In this issue of the JCI, Cui and colleagues identified TCF7-mediated canonical WNT signaling as a critical determinant of both the tumorigenicity and therapeutic function of ESC-derived retinal progenitor cells (ESC-RPCs). Their findings suggested that addressing key extracellular signaling and related intrinsic factors will be essential for the successful use of ESC-derived progenitor transplantation.
Collapse
Affiliation(s)
- Hong Ouyang
- Molecular Medicine Research Center and Department of Ophthalmology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | | | | |
Collapse
|
|
17
|
Zhao J, Luo J, Zhang K. Is Era of Ocular Regeneration Near? ASIA-PACIFIC JOURNAL OF OPHTHALMOLOGY (PHILADELPHIA, PA.) 2013; 2:71-2. [PMID: 26108040 DOI: 10.1097/apo.0b013e318290e20c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Jiagang Zhao
- From the *Department of Ophthalmology and Molecular Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China; Department of Ophthalmology,†Institute for Genomic Medicine and Shiley Eye Center, University of California San Diego, La Jolla, CA; ‡Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China; §Veterans Administration Healthcare System, San Diego, CA
| | | | | |
Collapse
|
|
18
|
Zhang K, Zhang L, Weinreb RN. Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma. Nat Rev Drug Discov 2012; 11:541-59. [PMID: 22699774 DOI: 10.1038/nrd3745] [Citation(s) in RCA: 246] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Blindness affects 60 million people worldwide. The leading causes of irreversible blindness include age-related macular degeneration, retinal vascular diseases and glaucoma. The unique features of the eye provide both benefits and challenges for drug discovery and delivery. During the past decade, the landscape for ocular drug therapy has substantially changed and our knowledge of the pathogenesis of ophthalmic diseases has grown considerably. Anti-angiogenic drugs have emerged as the most effective form of therapy for age-related macular degeneration and retinal vascular diseases. Lowering intraocular pressure is still the mainstay for glaucoma treatment but neuroprotective drugs represent a promising next-generation therapy. This Review discusses the current state of ocular drug therapy and highlights future therapeutic opportunities.
Collapse
Affiliation(s)
- Kang Zhang
- Department of Ophthalmology and Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
| | | | | |
Collapse
|
|
19
|
Nita M, Strzałka-Mrozik B, Grzybowski A, Romaniuk W, Mazurek U. Ophthalmic transplantology: posterior segment of the eye--part II. Med Sci Monit 2012; 18:RA97-103. [PMID: 22648265 PMCID: PMC3560715 DOI: 10.12659/msm.882868] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Background Transplants of the retina are among the new strategies being used in the treatment of genetic and degenerative macular diseases. Moreover, various cell cultures are being tested to treat retinal disorders. Material/Methods Literature dated from 2004 to 2011 was comprehensively examined via Medline and PubMed searches for the following terms: auto-, homo-, heterologous transplantation, retina, stem cells, cultivated cells. Results Tissue and cell therapy of retinal diseases are reviewed, including full-thickness retina/retinal pigment epithelium (RPE)/choroid graft; full and partial thickness RPE/choroid complex grafts; RPE/Bruch membrane complex graft; and RPE, iris pigment epithelium and stem cell grafts. Recommendations for transplants, as well as the benefits and weaknesses of specific techniques in retina transplants, are discussed. Conclusions Auto- and allogenic transplants of a full or partial thickness retina/RPE/Bruch membrane/choroid complex represent an alternative treatment offered to patients with some macular diseases. Stem cell transplantation to reconstruct and regenerate the macula requires further biomolecular and animal research studies.
Collapse
Affiliation(s)
- Małgorzata Nita
- Domestic and Specialized Medicine Centre Dilmed, Katowice, Poland
| | | | | | | | | |
Collapse
|