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In vitro stem cell modelling demonstrates a proof-of-concept for excess functional mutant TIMP3 as the cause of Sorsby fundus dystrophy.

التفاصيل البيبلوغرافية
العنوان: In vitro stem cell modelling demonstrates a proof-of-concept for excess functional mutant TIMP3 as the cause of Sorsby fundus dystrophy.
المؤلفون: Hongisto H; Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.; Faculty of Medicine and Health Technology, BioMediTech, Tampere University, Tampere, Finland., Dewing JM; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK., Christensen DR; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK., Scott J; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK., Cree AJ; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK., Nättinen J; SILK, Department of Ophthalmology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland., Määttä J; SILK, Department of Ophthalmology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland., Jylhä A; SILK, Department of Ophthalmology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland., Aapola U; SILK, Department of Ophthalmology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland., Uusitalo H; SILK, Department of Ophthalmology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.; Tays Eye Centre, Tampere University Hospital, Tampere, Finland., Kaarniranta K; Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.; Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland., Ratnayaka JA; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK., Skottman H; Faculty of Medicine and Health Technology, BioMediTech, Tampere University, Tampere, Finland., Lotery AJ; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
المصدر: The Journal of pathology [J Pathol] 2020 Oct; Vol. 252 (2), pp. 138-150. Date of Electronic Publication: 2020 Jul 31.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: John Wiley And Sons Country of Publication: England NLM ID: 0204634 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-9896 (Electronic) Linking ISSN: 00223417 NLM ISO Abbreviation: J Pathol Subsets: MEDLINE
أسماء مطبوعة: Publication: Chichester : John Wiley And Sons
Original Publication: London, Oliver & Boyd.
مواضيع طبية MeSH: Macular Degeneration/*pathology , Retinal Pigment Epithelium/*pathology , Tissue Inhibitor of Metalloproteinase-3/*genetics , Tissue Inhibitor of Metalloproteinase-3/*metabolism, Adult ; Cells, Cultured ; Female ; Humans ; In Vitro Techniques ; Induced Pluripotent Stem Cells ; Macular Degeneration/genetics ; Macular Degeneration/metabolism ; Middle Aged ; Mutation ; Proof of Concept Study ; Retinal Pigment Epithelium/metabolism
مستخلص: Sorsby fundus dystrophy (SFD) is a rare autosomal dominant disease of the macula that leads to bilateral loss of central vision and is caused by mutations in the TIMP3 gene. However, the mechanisms by which TIMP3 mutations cause SFD are poorly understood. Here, we generated human induced pluripotent stem cell-derived retinal pigmented epithelial (hiPSC-RPE) cells from three SFD patients carrying TIMP3 p.(Ser204Cys) and three non-affected controls to study disease-related structural and functional differences in the RPE. SFD-hiPSC-RPE exhibited characteristic RPE structure and physiology but showed significantly reduced transepithelial electrical resistance associated with enriched expression of cytoskeletal remodelling proteins. SFD-hiPSC-RPE exhibited basolateral accumulation of TIMP3 monomers, despite no change in TIMP3 gene expression. TIMP3 dimers were observed in both SFD and control hiPSC-RPE, suggesting that mutant TIMP3 dimerisation does not drive SFD pathology. Furthermore, mutant TIMP3 retained matrix metalloproteinase activity. Proteomic profiling showed increased expression of ECM proteins, endothelial cell interactions and angiogenesis-related pathways in SFD-hiPSC-RPE. By contrast, there were no changes in VEGF secretion. However, SFD-hiPSC-RPE secreted higher levels of monocyte chemoattractant protein 1, PDGF and angiogenin. Our findings provide a proof-of-concept that SFD patient-derived hiPSC-RPE mimic mature RPE cells and support the hypothesis that excess accumulation of mutant TIMP3, rather than an absence or deficiency of functional TIMP3, drives ECM and angiogenesis-related changes in SFD. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
(© 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
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فهرسة مساهمة: Keywords: Sorsby fundus dystrophy; human induced pluripotent stem cell; metalloproteinase inhibitor 3; retinal degeneration; retinal pigment epithelial cell
المشرفين على المادة: 0 (TIMP3 protein, human)
0 (Tissue Inhibitor of Metalloproteinase-3)
SCR Disease Name: Fundus Dystrophy, Pseudoinflammatory, Of Sorsby
تواريخ الأحداث: Date Created: 20200716 Date Completed: 20201214 Latest Revision: 20201214
رمز التحديث: 20221213
DOI: 10.1002/path.5506
PMID: 32666594
قاعدة البيانات: MEDLINE
الوصف
تدمد:1096-9896
DOI:10.1002/path.5506