المؤلفون: William D. B. Lamb, Karen Eastlake, Joshua Luis, Najam A. Sharif, Peng T. Khaw, G. Astrid Limb

المصدر: Frontiers in Cellular Neuroscience, Vol 17 (2024)

مصطلحات موضوعية: retina, Müller glia, extracellular vesicles, microRNA, neuroprotection, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: IntroductionAs with any other radial glia in the central nervous system, Müller glia derive from the same neuroepithelial precursors, perform similar functions, and exhibit neurogenic properties as radial glia in the brain. Müller glial cells retain progenitor-like characteristics in the adult human eye and can partially restore visual function upon intravitreal transplantation into animal models of glaucoma. Recently, it has been demonstrated that intracellular communication is possible via the secretion of nano-sized membrane-bound extracellular vesicles (EV), which contain bioactive molecules like microRNA (miRNA) and proteins that induce phenotypic changes when internalised by recipient cells.MethodsWe conducted high-throughput sequencing to profile the microRNA signature of EV populations secreted by Müller glia in culture and used bioinformatics tools to evaluate their potential role in the neuroprotective signalling attributed to these cells.ResultsSequencing of miRNA within Müller EV suggested enrichment with species associated with stem cells such as miR-21 and miR-16, as well as with miRNA previously found to play a role in diverse Müller cell functions in the retina: miR-9, miR-125b, and the let-7 family. A total of 51 miRNAs were found to be differentially enriched in EV compared to the whole cells from which EV originated. Bioinformatics analyses also indicated that preferential enrichment of species was demonstrated to regulate genes involved in cell proliferation and survival, including PTEN, the master inhibitor of the PI3K/AKT pathway.DiscussionThe results suggest that the release by Müller cells of miRNA-enriched EV abundant in species that regulate anti-apoptotic signalling networks is likely to represent a significant proportion of the neuroprotective effect observed after the transplantation of these cells into animal models of retinal ganglion cell (RGC) depletion. Future studies will seek to evaluate the modulation of putative genes as well as the activation of these pathways in in vitro and in vivo models following the internalisation of Müller-EV by target retinal neurons.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fncel.2023.1325114/fullTest; https://doaj.org/toc/1662-5102Test

الوصول الحر: https://doaj.org/article/9ecf20fce74d49e7adbb0f170f740a47Test

المؤلفون: Karen Eastlake, Joshua Luis, Weixin Wang, William Lamb, Peng T. Khaw, G. Astrid Limb

المصدر: Scientific Reports, Vol 13, Iss 1, Pp 1-15 (2023)

مصطلحات موضوعية: Medicine, Science

الوصف: Abstract Müller glia play very important and diverse roles in retinal homeostasis and disease. Although much is known of the physiological and morphological properties of mammalian Müller glia, there is still the need to further understand the profile of these cells during human retinal development. Using human embryonic stem cell-derived retinal organoids, we investigated the transcriptomic profiles of CD29+/CD44+ cells isolated from early and late stages of organoid development. Data showed that these cells express classic markers of retinal progenitors and Müller glia, including NFIX, RAX, PAX6, VSX2, HES1, WNT2B, SOX, NR2F1/2, ASCL1 and VIM, as early as days 10–20 after initiation of retinal differentiation. Expression of genes upregulated in CD29+/CD44+ cells isolated at later stages of organoid development (days 50–90), including NEUROG1, VSX2 and ASCL1 were gradually increased as retinal organoid maturation progressed. Based on the current observations that CD24+/CD44+ cells share the characteristics of early and late-stage retinal progenitors as well as of mature Müller glia, we propose that these cells constitute a single cell population that upon exposure to developmental cues regulates its gene expression to adapt to functions exerted by Müller glia in the postnatal and mature retina.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-2322Test

الوصول الحر: https://doaj.org/article/6507aa18b2f64bfb83eea7bc1e220b0dTest

المؤلفون: Puya Gharahkhani, Eric Jorgenson, Pirro Hysi, Anthony P. Khawaja, Sarah Pendergrass, Xikun Han, Jue Sheng Ong, Alex W. Hewitt, Ayellet V. Segrè, John M. Rouhana, Andrew R. Hamel, Robert P. Igo, Helene Choquet, Ayub Qassim, Navya S. Josyula, Jessica N. Cooke Bailey, Pieter W. M. Bonnemaijer, Adriana Iglesias, Owen M. Siggs, Terri L. Young, Veronique Vitart, Alberta A. H. J. Thiadens, Juha Karjalainen, Steffen Uebe, Ronald B. Melles, K. Saidas Nair, Robert Luben, Mark Simcoe, Nishani Amersinghe, Angela J. Cree, Rene Hohn, Alicia Poplawski, Li Jia Chen, Shi-Song Rong, Tin Aung, Eranga Nishanthie Vithana, NEIGHBORHOOD consortium, ANZRAG consortium, Biobank Japan project, FinnGen study, UK Biobank Eye and Vision Consortium, GIGA study group, and Me Research Team, Gen Tamiya, Yukihiro Shiga, Masayuki Yamamoto, Toru Nakazawa, Hannah Currant, Ewan Birney, Xin Wang, Adam Auton, Michelle K. Lupton, Nicholas G. Martin, Adeyinka Ashaye, Olusola Olawoye, Susan E. Williams, Stephen Akafo, Michele Ramsay, Kazuki Hashimoto, Yoichiro Kamatani, Masato Akiyama, Yukihide Momozawa, Paul J. Foster, Peng T. Khaw, James E. Morgan, Nicholas G. Strouthidis, Peter Kraft, Jae H. Kang, Chi Pui Pang, Francesca Pasutto, Paul Mitchell, Andrew J. Lotery, Aarno Palotie, Cornelia van Duijn, Jonathan L. Haines, Chris Hammond, Louis R. Pasquale, Caroline C. W. Klaver, Michael Hauser, Chiea Chuen Khor, David A. Mackey, Michiaki Kubo, Ching-Yu Cheng, Jamie E. Craig, Stuart MacGregor, Janey L. Wiggs

المصدر: Nature Communications, Vol 12, Iss 1, Pp 1-16 (2021)

مصطلحات موضوعية: Science

الوصف: Primary open-angle glaucoma (POAG) is highly heritable, yet not well understood from a genetic perspective. Here, the authors perform a meta-analysis of genome-wide association studies in 34,179 POAG cases, identifying 44 previously unreported risk loci and mapping effects across multiple ethnicities.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/ea46188f0f2c4f0cae58f959caf971a2Test

المؤلفون: Ana Patricia Marques, Jacqueline Ramke, John Cairns, Thomas Butt, Justine H. Zhang, Iain Jones, Marty Jovic, Allyala Nandakumar, Hannah Faal, Hugh Taylor, Andrew Bastawrous, Tasanee Braithwaite, Serge Resnikoff, Peng T. Khaw, Rupert Bourne, Iris Gordon, Kevin Frick, Matthew J. Burton

المصدر: EClinicalMedicine, Vol 46, Iss , Pp 101354- (2022)

مصطلحات موضوعية: Ophthalmology, Public health, Health economics, Systematic review, Medicine (General), R5-920

الوصف: Summary: Vision impairment (VI) can have wide ranging economic impact on individuals, households, and health systems. The aim of this systematic review was to describe and summarise the costs associated with VI and its major causes. We searched MEDLINE (16 November 2019), National Health Service Economic Evaluation Database, the Database of Abstracts of Reviews of Effects and the Health Technology Assessment database (12 December 2019) for partial or full economic evaluation studies, published between 1 January 2000 and the search dates, reporting cost data for participants with VI due to an unspecified cause or one of the seven leading causes globally: cataract, uncorrected refractive error, diabetic retinopathy, glaucoma, age-related macular degeneration, corneal opacity, trachoma. The search was repeated on 20 January 2022 to identify studies published since our initial search. Included studies were quality appraised using the British Medical Journal Checklist for economic submissions adapted for cost of illness studies. Results were synthesized in a structured narrative. Of the 138 included studies, 38 reported cost estimates for VI due to an unspecified cause and 100 reported costs for one of the leading causes. These 138 studies provided 155 regional cost estimates. Fourteen studies reported global data; 103/155 (66%) regional estimates were from high-income countries. Costs were most commonly reported using a societal (n = 48) or healthcare system perspective (n = 25). Most studies included only a limited number of cost components. Large variations in methodology and reporting across studies meant cost estimates varied considerably. The average quality assessment score was 78% (range 35–100%); the most common weaknesses were the lack of sensitivity analysis and insufficient disaggregation of costs. There was substantial variation across studies in average treatment costs per patient for most conditions, including refractive error correction (range $12–$201 ppp), cataract surgery (range $54–$3654 ppp), glaucoma (range $351–$1354 ppp) and AMD (range $2209–$7524 ppp). Future cost estimates of the economic burden of VI and its major causes will be improved by the development and adoption of a reference case for eye health. This could then be used in regular studies, particularly in countries with data gaps, including low- and middle-income countries in Asia, Eastern Europe, Oceania, Latin America and sub-Saharan Africa.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2589537022000840Test; https://doaj.org/toc/2589-5370Test

الوصول الحر: https://doaj.org/article/476d3d14b9a74e4e91886a63bf244658Test

المؤلفون: Karen Eastlake, Weixin Wang, Hari Jayaram, Celia Murray‐Dunning, Amanda J. F. Carr, Conor M. Ramsden, Anthony Vugler, Katrina Gore, Nadine Clemo, Mark Stewart, Pete Coffey, Peng T. Khaw, G. Astrid Limb

المصدر: Stem Cells Translational Medicine, Vol 8, Iss 8, Pp 775-784 (2019)

مصطلحات موضوعية: Stem cells, Induced pluripotent stem cell, Müller glia, Glaucoma, Regeneration, Medicine (General), R5-920, Cytology, QH573-671

الوصف: Abstract Glaucoma is one of the leading causes of blindness, and there is an ongoing need for new therapies. Recent studies indicate that cell transplantation using Müller glia may be beneficial, but there is a need for novel sources of cells to provide therapeutic benefit. In this study, we have isolated Müller glia from retinal organoids formed by human induced pluripotent stem cells (hiPSCs) in vitro and have shown their ability to partially restore visual function in rats depleted of retinal ganglion cells by NMDA. Based on the present results, we suggest that Müller glia derived from retinal organoids formed by hiPSC may provide an attractive source of cells for human retinal therapies, to prevent and treat vision loss caused by retinal degenerative conditions. Stem Cells Translational Medicine 2019;8:775&784

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2157-6564Test; https://doaj.org/toc/2157-6580Test

الوصول الحر: https://doaj.org/article/3318628640d742c6b2a42b2b510967aaTest

المؤلفون: Hannah Currant, Pirro Hysi, Tomas W. Fitzgerald, Puya Gharahkhani, Pieter W. M. Bonnemaijer, Anne Senabouth, Alex W. Hewitt, UK Biobank Eye and Vision Consortium, International Glaucoma Genetics Consortium, Denize Atan, Tin Aung, Jason Charng, Hélène Choquet, Jamie Craig, Peng T. Khaw, Caroline C. W. Klaver, Michiaki Kubo, Jue-Sheng Ong, Louis R. Pasquale, Charles A. Reisman, Maciej Daniszewski, Joseph E. Powell, Alice Pébay, Mark J. Simcoe, Alberta A. H. J. Thiadens, Cornelia M. van Duijn, Seyhan Yazar, Eric Jorgenson, Stuart MacGregor, Chris J. Hammond, David A. Mackey, Janey L. Wiggs, Paul J. Foster, Praveen J. Patel, Ewan Birney, Anthony P. Khawaja

المصدر: PLoS Genetics, Vol 17, Iss 10 (2021)

مصطلحات موضوعية: Genetics, QH426-470

وصف الملف: electronic resource

العلاقة: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523050/?tool=EBITest; https://doaj.org/toc/1553-7390Test; https://doaj.org/toc/1553-7404Test

الوصول الحر: https://doaj.org/article/64abaab7be3d461887d9446f188a5fb2Test

المؤلفون: Aristides D. Tagalakis, Shivam Madaan, Scott D. Larsen, Richard R. Neubig, Peng T. Khaw, Ian Rodrigues, Saurabh Goyal, Kin Sheng Lim, Cynthia Yu-Wai-Man

المصدر: Journal of Nanobiotechnology, Vol 16, Iss 1, Pp 1-11 (2018)

مصطلحات موضوعية: Nanocarrier, Sustained release, Inhibitor, Glaucoma, Fibrosis, Biotechnology, TP248.13-248.65, Medical technology, R855-855.5

الوصف: Abstract Background Sustained drug delivery is a large unmet clinical need in glaucoma. Here, we incorporated a Myocardin-Related Transcription Factor/Serum Response Factor inhibitor, CCG-222740, into slow release large unilamellar vesicles derived from the liposomes DOTMA (1,2-di-O-octadecenyl-3-trimethylammonium propane) and DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), and tested their effects in vitro and in vivo. Results The vesicles were spherical particles of around 130 nm and were strongly cationic. A large amount of inhibitor could be incorporated into the vesicles. We showed that the nanocarrier CCG-222740 formulation gradually released the inhibitor over 14 days using high performance liquid chromatography. Nanocarrier CCG-222740 significantly decreased ACTA2 gene expression and was not cytotoxic in human conjunctival fibroblasts. In vivo, nanocarrier CCG-222740 doubled the bleb survival from 11.0 ± 0.6 days to 22.0 ± 1.3 days (p = 0.001), decreased conjunctival scarring and did not have any local or systemic adverse effects in a rabbit model of glaucoma filtration surgery. Conclusions Our study demonstrates proof-of-concept that a nanocarrier-based formulation efficiently achieves a sustained release of a Myocardin-Related Transcription Factor/Serum Response Factor inhibitor and prevents conjunctival fibrosis in an established rabbit model of glaucoma filtration surgery.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s12951-018-0425-3Test; https://doaj.org/toc/1477-3155Test

الوصول الحر: https://doaj.org/article/01cbae81bc8b41f7bd5ccf2d64ab173fTest

المؤلفون: Cynthia Yu-Wai-Man, Nicholas Owen, Jonathan Lees, Aristides D. Tagalakis, Stephen L. Hart, Andrew R. Webster, Christine A. Orengo, Peng T. Khaw

المصدر: Scientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)

مصطلحات موضوعية: Medicine, Science

الوصف: Abstract Fibrosis-related events play a part in most blinding diseases worldwide. However, little is known about the mechanisms driving this complex multifactorial disease. Here we have carried out the first genome-wide RNA-Sequencing study in human conjunctival fibrosis. We isolated 10 primary fibrotic and 7 non-fibrotic conjunctival fibroblast cell lines from patients with and without previous glaucoma surgery, respectively. The patients were matched for ethnicity and age. We identified 246 genes that were differentially expressed by over two-fold and p

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-2322Test

الوصول الحر: https://doaj.org/article/5c0371687dca468ab80f8f19c7cf2ac1Test

المؤلفون: Cynthia Yu-Wai-Man, Bradley Spencer-Dene, Richard M. H. Lee, Kim Hutchings, Erika M. Lisabeth, Richard Treisman, Maryse Bailly, Scott D. Larsen, Richard R. Neubig, Peng T. Khaw

المصدر: Scientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)

مصطلحات موضوعية: Medicine, Science

الوصف: Abstract The myocardin-related transcription factor/serum response factor (MRTF/SRF) pathway represents a promising therapeutic target to prevent fibrosis. We have tested the effects of new pharmacological inhibitors of MRTF/SRF signalling in a preclinical model of fibrosis. CCG-222740, a novel MRTF/SRF inhibitor, markedly decreased SRF reporter gene activity and showed a greater inhibitory effect on MRTF/SRF target genes than the previously described MRTF-A inhibitor CCG-203971. CCG-222740 was also five times more potent, with an IC50 of 5 μM, in a fibroblast-mediated collagen contraction assay, was less cytotoxic, and a more potent inhibitor of alpha-smooth muscle actin protein expression than CCG-203971. Local delivery of CCG-222740 and CCG-203971 in a validated and clinically relevant rabbit model of scar tissue formation after glaucoma filtration surgery increased the long-term success of the surgery by 67% (P

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-2322Test

الوصول الحر: https://doaj.org/article/d0d09e6ee5ac462a80dbec12fafe4e2cTest

المؤلفون: Gianluca Scuderi, Peng T. Khaw, Felipe A. Medeiros, Gianluca Manni

المصدر: Journal of Ophthalmology, Vol 2016 (2016)

مصطلحات موضوعية: Ophthalmology, RE1-994

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2090-004XTest; https://doaj.org/toc/2090-0058Test

الوصول الحر: https://doaj.org/article/09be8b0a2c704237a5281184be4a2642Test