{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T08:59:20Z","timestamp":1792659560375,"version":"4.5.0"},"reference-count":69,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"37","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2021,9,10]]},"abstract":"<jats:p>\n            Duchenne muscular dystrophy (DMD) is caused by\n            <jats:italic>dystrophin<\/jats:italic>\n            gene mutations leading to skeletal muscle weakness and wasting. Dystrophin is enriched at the neuromuscular junction (NMJ), but how NMJ abnormalities contribute to DMD pathogenesis remains unclear. Here, we combine transcriptome analysis and modeling of DMD patient-derived neuromuscular circuits with CRISPR-corrected isogenic controls in compartmentalized microdevices. We show that NMJ volumes and optogenetic motor neuron\u2013stimulated myofiber contraction are compromised in DMD neuromuscular circuits, which can be rescued by pharmacological inhibition of TGF\u03b2 signaling, an observation validated in a 96-well human neuromuscular circuit coculture assay. These beneficial effects are associated with normalization of dysregulated gene expression in DMD myogenic transcriptomes affecting NMJ assembly (e.g.,\n            <jats:italic>MUSK<\/jats:italic>\n            ) and axon guidance (e.g.,\n            <jats:italic>SLIT2<\/jats:italic>\n            and\n            <jats:italic>SLIT3<\/jats:italic>\n            ). Our study provides a new human microphysiological model for investigating NMJ defects in DMD and assessing candidate drugs and suggests that enhancing neuromuscular connectivity may be an effective therapeutic strategy.\n          <\/jats:p>","DOI":"10.1126\/sciadv.abi8787","type":"journal-article","created":{"date-parts":[[2021,9,10]],"date-time":"2021-09-10T17:55:34Z","timestamp":1631296534000},"source":"Crossref","is-referenced-by-count":20,"title":["Optogenetic modeling of human neuromuscular circuits in Duchenne muscular dystrophy with CRISPR and pharmacological corrections"],"prefix":"10.1126","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9504-8423","authenticated-orcid":true,"given":"Amaia","family":"Paredes-Redondo","sequence":"first","affiliation":[{"name":"Centre for Genomics and Child Health, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK."},{"name":"Stem Cell Laboratory, National Bowel Research Centre, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 2 Newark Street, London E1 2AT, UK."},{"name":"Centre for Predictive in vitro Model, Queen Mary University of London, Mile End Road, London E1 4NS, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6689-0227","authenticated-orcid":true,"given":"Peter","family":"Harley","sequence":"additional","affiliation":[{"name":"Centre for Stem Cells and Regenerative Medicine, MRC Centre for Neurodevelopmental Disorders, and Centre for Developmental Neurobiology, King\u2019s College London, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Maniati","sequence":"additional","affiliation":[{"name":"Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8906-2379","authenticated-orcid":true,"given":"David","family":"Ryan","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2245-8453","authenticated-orcid":true,"given":"Sandra","family":"Louzada","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8405-8140","authenticated-orcid":true,"given":"Jinhong","family":"Meng","sequence":"additional","affiliation":[{"name":"UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2887-0393","authenticated-orcid":true,"given":"Anna","family":"Kowala","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Child Health, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK."},{"name":"Stem Cell Laboratory, National Bowel Research Centre, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 2 Newark Street, London E1 2AT, UK."},{"name":"Centre for Predictive in vitro Model, Queen Mary University of London, Mile End Road, London E1 4NS, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beiyuan","family":"Fu","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3573-2354","authenticated-orcid":true,"given":"Fengtang","family":"Yang","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5774-9678","authenticated-orcid":true,"given":"Pentao","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Marino","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Child Health, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5189-1227","authenticated-orcid":true,"given":"Olivier","family":"Pourqui\u00e9","sequence":"additional","affiliation":[{"name":"Department of Genetics and Department of Pathology, Brigham and Women\u2019s Hospital, Harvard Medical School, 60 Fenwood Road, Boston, MA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9102-5232","authenticated-orcid":true,"given":"Francesco","family":"Muntoni","sequence":"additional","affiliation":[{"name":"UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK."},{"name":"NIHR Biomedical Research Centre, Great Ormond Street Hospital, Great Ormond Street, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2509-9599","authenticated-orcid":true,"given":"Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3539-3054","authenticated-orcid":true,"given":"Ivo","family":"Lieberam","sequence":"additional","affiliation":[{"name":"Centre for Stem Cells and Regenerative Medicine, MRC Centre for Neurodevelopmental Disorders, and Centre for Developmental Neurobiology, King\u2019s College London, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0435-7694","authenticated-orcid":true,"given":"Yung-Yao","family":"Lin","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Child Health, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK."},{"name":"Stem Cell Laboratory, National Bowel Research Centre, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 2 Newark Street, London E1 2AT, UK."},{"name":"Centre for Predictive in vitro Model, Queen Mary University of London, Mile End Road, London E1 4NS, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.23528"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/mus.1192"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(09)70271-6"},{"key":"e_1_3_3_5_2","first-page":"9","article-title":"Old and new therapeutic developments in steroid treatment in Duchenne muscular dystrophy","volume":"31","author":"Angelini C.","year":"2012","unstructured":"C. Angelini, E. Peterle, Old and new therapeutic developments in steroid treatment in Duchenne muscular dystrophy. Acta Myol. 31, 9\u201315 (2012).","journal-title":"Acta Myol."},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/mus.24332"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41434-020-0156-6"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1080\/14712598.2021.1832462"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-009-8089-5"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/97.1.123"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.13249"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2020.135304"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2020.103032"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.018424"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.11.008"},{"key":"e_1_3_3_16_2","doi-asserted-by":"crossref","unstructured":"A. Paredes-Redondo Y. Lin Human induced pluripotent stem cells: Challenges and opportunities in developing new therapies for muscular dystrophies in eLS (John Wiley & Sons 2019).","DOI":"10.1002\/9780470015902.a0028371"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.151035"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.05.016"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/adbi.201800307"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aat5847"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn1525"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature24052"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2019.07.003"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201947967"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2016.110"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19061546"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-74157-y"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1910456117"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2005.11.032"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1248523"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.5334\/jors.bl"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-017-0010-2"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-007-7034-x"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1177\/1756285610388693"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI7866"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05756"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-022516-034255"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80590-5"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a001842"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2016.01.021"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.12266"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1186\/2044-5040-1-19"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-014-1663-7"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2005.10.020"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1113\/JP277839"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20289-8"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.038711"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00007.2015"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12665"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.5966\/sctm.2015-0224"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10974-019-09535-9"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2018.02.013"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1186\/s10020-018-0024-7"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31611-2"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-019-0416-4"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0211384"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2015.08.012"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10424"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.03.028"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.097188"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0044261"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1502902112"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09160"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0700384104"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3317"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu638"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1093\/biostatistics\/kxr054"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1226"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0506-500"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.abi8787","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T17:59:40Z","timestamp":1704823180000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.abi8787"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,10]]},"references-count":69,"journal-issue":{"issue":"37","published-print":{"date-parts":[[2021,9,10]]}},"alternative-id":["10.1126\/sciadv.abi8787"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.abi8787","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,10]]},"article-number":"eabi8787"}}