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However, the mechanisms by which TIMP3<\/jats:italic> mutations cause SFD are poorly understood. Here, we generated human induced pluripotent stem cell\u2010derived retinal pigmented epithelial (hiPSC\u2010RPE) cells from three SFD patients carrying TIMP3 p.(Ser204Cys) and three non\u2010affected controls to study disease\u2010related structural and functional differences in the RPE. SFD\u2010hiPSC\u2010RPE exhibited characteristic RPE structure and physiology but showed significantly reduced transepithelial electrical resistance associated with enriched expression of cytoskeletal remodelling proteins. SFD\u2010hiPSC\u2010RPE exhibited basolateral accumulation of TIMP3 monomers, despite no change in TIMP3<\/jats:italic> gene expression. TIMP3 dimers were observed in both SFD and control hiPSC\u2010RPE, 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\u2010related pathways in SFD\u2010hiPSC\u2010RPE. By contrast, there were no changes in VEGF secretion. However, SFD\u2010hiPSC\u2010RPE secreted higher levels of monocyte chemoattractant protein 1, PDGF and angiogenin. Our findings provide a proof\u2010of\u2010concept that SFD patient\u2010derived hiPSC\u2010RPE 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\u2010related changes in SFD. \u00a9 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.5506","type":"journal-article","created":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T04:30:02Z","timestamp":1594787402000},"page":"138-150","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["In vitro<\/i> stem cell modelling demonstrates a proof\u2010of\u2010concept for excess functional mutant TIMP3<\/scp> as the cause of S<\/scp>orsby f<\/scp>undus d<\/scp>ystrophy"],"prefix":"10.1002","volume":"252","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2416-5673","authenticated-orcid":false,"given":"Heidi","family":"Hongisto","sequence":"first","affiliation":[{"name":"Department of Ophthalmology Institute of Clinical Medicine, University of Eastern Finland Kuopio Finland"},{"name":"Faculty of Medicine and Health Technology, BioMediTech Tampere University Tampere 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