{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T01:46:37Z","timestamp":1793411197996,"version":"4.5.0"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2021,11,10]],"date-time":"2021-11-10T00:00:00Z","timestamp":1636502400000},"content-version":"vor","delay-in-days":2365,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["098330\/Z\/12\/Z"],"award-info":[{"award-number":["098330\/Z\/12\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Trisomy 21 (T21), Down Syndrome (DS) is the most common genetic cause of dementia and intellectual disability. Modeling DS is beginning to yield pharmaceutical therapeutic interventions for amelioration of intellectual disability, which are currently being tested in clinical trials. DS is also a unique genetic system for investigation of pathological and protective mechanisms for accelerated ageing, neurodegeneration, dementia, cancer, and other important common diseases. New drugs could be identified and disease mechanisms better understood by establishment of well-controlled cell model systems. We have developed a first nonintegration-reprogrammed isogenic human induced pluripotent stem cell (iPSC) model of DS by reprogramming the skin fibroblasts from an adult individual with constitutional mosaicism for DS and separately cloning multiple isogenic T21 and euploid (D21) iPSC lines. Our model shows a very low number of reprogramming rearrangements as assessed by a high-resolution whole genome CGH-array hybridization, and it reproduces several cellular pathologies seen in primary human DS cells, as assessed by automated high-content microscopic analysis. Early differentiation shows an imbalance of the lineage-specific stem\/progenitor cell compartments: T21 causes slower proliferation of neural and faster expansion of hematopoietic lineage. T21 iPSC-derived neurons show increased production of amyloid peptide-containing material, a decrease in mitochondrial membrane potential, and an increased number and abnormal appearance of mitochondria. Finally, T21-derived neurons show significantly higher number of DNA double-strand breaks than isogenic D21 controls. Our fully isogenic system therefore opens possibilities for modeling mechanisms of developmental, accelerated ageing, and neurodegenerative pathologies caused by T21. Stem Cells \u00a02015;33:2077\u20132084<\/jats:p>\n                  <jats:p>Video Highlight: https:\/\/youtu.be\/MoMwXg2azGo<\/jats:p>","DOI":"10.1002\/stem.1968","type":"journal-article","created":{"date-parts":[[2015,2,19]],"date-time":"2015-02-19T00:52:54Z","timestamp":1424307174000},"page":"2077-2084","source":"Crossref","is-referenced-by-count":84,"title":["Brief Report: Isogenic Induced Pluripotent Stem Cell Lines From an Adult With Mosaic Down Syndrome Model Accelerated Neuronal Ageing and Neurodegeneration"],"prefix":"10.1093","volume":"33","author":[{"given":"Aoife","family":"Murray","sequence":"first","affiliation":[{"name":"The Blizard Institute Barts and The London School of Medicine, London, United Kingdom"},{"name":"The LonDownS Consortium, Wellcome Trust, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Letourneau","sequence":"additional","affiliation":[{"name":"Department of Genetic Medicine and Development 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Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Abrehart","sequence":"additional","affiliation":[{"name":"The Blizard Institute Barts and The London School of Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pollyanna","family":"Goh","sequence":"additional","affiliation":[{"name":"The Blizard Institute Barts and The London School of Medicine, London, United Kingdom"},{"name":"The LonDownS Consortium, Wellcome Trust, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhui","family":"Lim","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Baldo","sequence":"additional","affiliation":[{"name":"Human Genetics Laboratory, Galliera Hospital, Genoa, 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Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Syndercombe Court","sequence":"additional","affiliation":[{"name":"Department of Forensic and Analytical Science King's College, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noemi","family":"Fusaki","sequence":"additional","affiliation":[{"name":"Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamoru","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"DNAVEC Corporation, Ibaraki, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor G.","family":"Smart","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cleo","family":"Bishop","sequence":"additional","affiliation":[{"name":"The Blizard Institute Barts and The London School of Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stylianos E.","family":"Antonarakis","sequence":"additional","affiliation":[{"name":"Department of Genetic Medicine and Development University of Geneva Medical School, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Groet","sequence":"additional","affiliation":[{"name":"The Blizard Institute Barts and The London School of Medicine, London, United Kingdom"},{"name":"The LonDownS Consortium, Wellcome Trust, London, United Kingdom"},{"name":"Stem Cell Laboratory, National Centre for Bowel Research and Surgical Innovation, Queen Mary University of London, London, United 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