دورية أكاديمية
In vitro stem cell modelling demonstrates a proof-of-concept for excess functional mutant TIMP3 as the cause of Sorsby fundus dystrophy.
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.) |
References: | Christensen DRG, Brown FE, Cree AJ, et al. Sorsby fundus dystrophy - a review of pathology and disease mechanisms. Exp Eye Res 2017; 165: 35-46. Anand-Apte B, Chao JR, Singh R, et al. Sorsby fundus dystrophy: insights from the past and looking to the future. J Neurosci Res 2019; 97: 88-97. Fritsche LG, Igl W, Bailey JNC, et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet 2016; 48: 134-143. Gliem M, Müller PL, Mangold E, et al. Reticular pseudodrusen in Sorsby fundus dystrophy. Ophthalmology 2015; 122: 1555-1562. Hussain AA, Starita C, Hodgetts A, et al. Macromolecular diffusion characteristics of ageing human Bruch's membrane: implications for age-related macular degeneration (AMD). Exp Eye Res 2010; 90: 703-710. Curcio CA, Johnson M. Structure, function, and pathology of Bruch's membrane. In Retina (5th edn), Sadda S (Ed). Elsevier: Oxford, 2012; 465-481. Gemenetzi MK, Luff AJ, Lotery AJ. Successful treatment of choroidal neovascularization secondary to Sorsby fundus dystrophy with intravitreal bevacizumab. Retin Cases Brief Rep 2011; 5: 132-135. Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta 2010; 1803: 55-71. Dewing JM, Carare RO, Lotery AJ, et al. The diverse roles of TIMP-3: insights into degenerative diseases of the senescent retina and brain. Cells 2019; 9: 39. Naessens S, De Zaeytijd J, Syx D, et al. The N-terminal p.(Ser38Cys) TIMP3 mutation underlying Sorsby fundus dystrophy is a founder mutation disrupting an intramolecular disulfide bond. Hum Mutat 2019; 40: 539-551. Qi JH, Ebrahem Q, Yeow K, et al. Expression of Sorsby's fundus dystrophy mutations in human retinal pigment epithelial cells reduces matrix metalloproteinase inhibition and may promote angiogenesis. J Biol Chem 2002; 277: 13394-13400. Weber BHF, Lin B, White K, et al. A mouse model for Sorsby fundus dystrophy. Invest Ophthalmol Vis Sci 2002; 43: 2732-2740. Galloway CA, Dalvi S, Hung SSC, et al. Drusen in patient-derived hiPSC-RPE models of macular dystrophies. Proc Natl Acad Sci U S A 2017; 114: E8214-E8223. Sorkio A, Hongisto H, Kaarniranta K, et al. Structure and barrier properties of human embryonic stem cell-derived retinal pigment epithelial cells are affected by extracellular matrix protein coating. Tissue Eng Part A 2014; 20: 622-634. Vähätupa M, Nättinen J, Jylhä A, et al. SWATH-MS proteomic analysis of oxygen-induced retinopathy reveals novel potential therapeutic targets. Invest Ophthalmol Vis Sci 2018; 59: 3294-3306. Nättinen J, Jylhä A, Aapola U, et al. Topical fluorometholone treatment and desiccating stress change inflammatory protein expression in tears. Ocul Surf 2018; 16: 84-92. Ortmann D, Vallier L. Variability of human pluripotent stem cell lines. Curr Opin Genet Dev 2017; 46: 179-185. Ivanov AI, Parkos CA, Nusrat A. Cytoskeletal regulation of epithelial barrier function during inflammation. Am J Pathol 2010; 177: 512-524. Tarau I, Berlin A, Curcio CA, et al. The cytoskeleton of the retinal pigment epithelium: from normal aging to age-related macular degeneration. Int J Mol Sci 2019; 20: 3578. Paige MF, Rainey JK, Goh MC. Fibrous long spacing collagen ultrastructure elucidated by atomic force microscopy. Biophys J 1998; 74: 3211-3216. Curcio CA, Millican CL. Basal linear deposit and large drusen are specific for early age-related maculopathy. Arch Ophthalmol 1999; 117: 329-339. Chong NHV, Kvanta A, Seregard S, et al. TIMP-3 mRNA is not overexpressed in Sorsby fundus dystrophy. Am J Ophthalmol 2003; 136: 954-955. Arris CE, Bevitt DJ, Mohamed J, et al. Expression of mutant and wild-type TIMP3 in primary gingival fibroblasts from Sorsby's fundus dystrophy patients. Biochim Biophys Acta 2003; 1638: 20-28. Langton KP, Barker MD, McKie N. Localization of the functional domains of human tissue inhibitor of metalloproteinases-3 and the effects of a Sorsby's fundus dystrophy mutation. J Biol Chem 1998; 273: 16778-16781. Yeow KM, Kishnani NS, Hutton M, et al. Sorsby's fundus dystrophy tissue inhibitor of metalloproteinases-3 (TIMP-3) mutants have unimpaired matrix metalloproteinase inhibitory activities, but affect cell adhesion to the extracellular matrix. Matrix Biol 2002; 21: 75-88. Qi JH, Dai G, Luthert P, et al. S156C mutation in tissue inhibitor of metalloproteinases-3 induces increased angiogenesis. J Biol Chem 2009; 284: 19927-19936. Lambert V, Wielockx B, Munaut C, et al. MMP-2 and MMP-9 synergize in promoting choroidal neovascularization. FASEB J 2003; 17: 2290-2292. Chau KY, Sivaprasad S, Patel N, et al. Plasma levels of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9) in age-related macular degeneration. Eye (Lond) 2007; 21: 1511-1515. Hussain AA, Lee Y, Zhang J, et al. Disturbed matrix metalloproteinase pathway in both age-related macular degeneration and Alzheimer's disease. J Neurodegener Dis 2017; 2017: 4810232. Capon MR, Marshall J, Krafft JI, et al. Sorsby's fundus dystrophy. A light and electron microscopic study. Ophthalmology 1989; 96: 1769-1777. Stone EM, Lotery AJ, Munier FL, et al. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nat Genet 1999; 22: 199-202. Zhang Y, Marmorstein LY. Focus on molecules: fibulin-3 (EFEMP1). Exp Eye Res 2010; 90: 374-375. Hulleman JD, Kaushal S, Balch WE, et al. Compromised mutant EFEMP1 secretion associated with macular dystrophy remedied by proteostasis network alteration. Mol Biol Cell 2011; 22: 4765-4775. Marmorstein LY, Munier FL, Arsenijevic Y, et al. Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration. Proc Natl Acad Sci U S A 2002; 99: 13067-13072. Stanton JB, Marmorstein AD, Zhang Y, et al. Deletion of Efemp1 is protective against the development of sub-RPE deposits in mouse eyes. Invest Ophthalmol Vis Sci 2017; 58: 1455-1461. Roybal CN, Marmorstein LY, Vander Jagt DL, et al. Aberrant accumulation of fibulin-3 in the endoplasmic reticulum leads to activation of the unfolded protein response and VEGF expression. Invest Ophthalmol Vis Sci 2005; 46: 3973-3979. Klenotic PA, Munier FL, Marmorstein LY, et al. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a binding partner of epithelial growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1). Implications for macular degenerations. J Biol Chem 2004; 279: 30469-30473. Fu L, Garland D, Yang Z, et al. The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice. Hum Mol Genet 2007; 16: 2411-2422. Fernandez-Godino R, Bujakowska KM, Pierce EA. Changes in extracellular matrix cause RPE cells to make basal deposits and activate the alternative complement pathway. Hum Mol Genet 2018; 27: 147-159. Castelli V, d'Angelo M, Antonosante A, et al. Physiology and pathophysiology of PPARs in the eye. Nucl Recept Res 2018; 5: 1-17. Rutar M, Natoli R, Valter K, et al. Early focal expression of the chemokine Ccl2 by Müller cells during exposure to damage-inducing bright continuous light. Invest Ophthalmol Vis Sci 2011; 52: 2379-2388. Bonyadi M, Jabbarpoor Bonyadi MH, Yaseri M, et al. Joint association of complement component 3 and CC-cytokine ligand2 (CCL2) or complement component 3 and CFH polymorphisms in age-related macular degeneration. Ophthalmic Genet 2017; 38: 365-370. Sharma NK, Sharma K, Singh R, et al. CCL2 single nucleotide polymorphism of rs1024611 implicates prominence of inflammatory cascade by univariate modeling in Indian AMD. PLoS One 2018; 13: e0193423. El Khoury J, Toft M, Hickman SE, et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 2007; 13: 432-438. Qi JH, Ebrahem Q, Moore N, et al. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med 2003; 9: 407-415. Qi JH, Ebrahem Q, Ali M, et al. Tissue inhibitor of metalloproteinases-3 peptides inhibit angiogenesis and choroidal neovascularization in mice. PLoS One 2013; 8: e55667. Fogarasi M, Janssen A, Weber BHF, et al. Molecular dissection of TIMP3 mutation S156C associated with Sorsby fundus dystrophy. Matrix Biol 2008; 27: 381-392. Chen Y, Brown NJ, Jones R, et al. A peptide derived from TIMP-3 inhibits multiple angiogenic growth factor receptors and tumour growth and inflammatory arthritis in mice. Angiogenesis 2014; 17: 207-219. Calejo MT, Saari J, Vuorenpää H, et al. Co-culture of human induced pluripotent stem cell-derived retinal pigment epithelial cells and endothelial cells on double collagen-coated honeycomb films. Acta Biomater 2019; 101: 327-343. Song MJ, Bharti K. Looking into the future: using induced pluripotent stem cells to build two and three dimensional ocular tissue for cell therapy and disease modeling. Brain Res 2016; 1638: 2-14. Hongisto H, Ilmarinen T, Vattulainen M, et al. Xeno- and feeder-free differentiation of human pluripotent stem cells to two distinct ocular epithelial cell types using simple modifications of one method. Stem Cell Res Ther 2017; 8: 291. Hakala H, Rajala K, Ojala M, et al. Comparison of biomaterials and extracellular matrices as a culture platform for multiple, independently derived human embryonic stem cell lines. Tissue Eng Part A 2009; 15: 1775-1785. Zhang WY, de Almeida PE, Wu JC. Teratoma formation: a tool for monitoring pluripotency in stem cell research. In StemBook. Harvard Stem Cell Institute: Cambridge, 2012. [Accessed 26 June 2020]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK133287/. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402-408. Huang DW, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009; 4: 44-57. Huang DW, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 2009; 37: 1-13. Bates D, Machler M, Bolker B, et al. Fitting linear mixed-effects models using lme4. J Stat Softw 2015; 67: 1-48. |
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 |
تدمد: | 1096-9896 |
---|---|
DOI: | 10.1002/path.5506 |