{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T14:53:48Z","timestamp":1793199228421,"version":"4.5.0"},"reference-count":67,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T00:00:00Z","timestamp":1640995200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Jesse\u2019s Journey Foundation"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL149734"],"award-info":[{"award-number":["HL149734"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32EB001650"],"award-info":[{"award-number":["T32EB001650"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["CMMI-1661730"],"award-info":[{"award-number":["CMMI-1661730"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DGE-1762114"],"award-info":[{"award-number":["DGE-1762114"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center","award":["P50AR065139"],"award-info":[{"award-number":["P50AR065139"]}]},{"name":"UW Institute for Stem Cell and Regenerative Medicine","award":["Innovation Pilot Award"],"award-info":[{"award-number":["Innovation Pilot Award"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Tissue Eng"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:p>\n                    Cardiomyopathy is currently the leading cause of death for patients with Duchenne muscular dystrophy (DMD), a severe neuromuscular disorder affecting young boys. Animal models have provided insight into the mechanisms by which dystrophin protein deficiency causes cardiomyopathy, but there remains a need to develop human models of DMD to validate pathogenic mechanisms and identify therapeutic targets. Here, we have developed human engineered heart tissues (EHTs) from CRISPR-edited, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) expressing a truncated dystrophin protein lacking part of the actin-binding domain. The 3D EHT platform enables direct measurement of contractile force, simultaneous monitoring of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transients, and assessment of myofibril structure. Dystrophin-mutant EHTs produced less contractile force as well as delayed kinetics of force generation and relaxation, as compared to isogenic controls. Contractile dysfunction was accompanied by reduced sarcomere length, increased resting cytosolic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    levels, delayed Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release and reuptake, and increased beat rate irregularity. Transcriptomic analysis revealed clear differences between dystrophin-deficient and control EHTs, including downregulation of genes related to Ca\n                    <jats:sup>2+<\/jats:sup>\n                    homeostasis and extracellular matrix organization, and upregulation of genes related to regulation of membrane potential, cardiac muscle development, and heart contraction. These findings indicate that the EHT platform provides the cues necessary to expose the clinically-relevant, functional phenotype of force production as well as mechanistic insights into the role of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    handling and transcriptomic dysregulation in dystrophic cardiac function, ultimately providing a powerful platform for further studies in disease modeling and drug discovery.\n                  <\/jats:p>","DOI":"10.1177\/20417314221119628","type":"journal-article","created":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T07:46:19Z","timestamp":1660722379000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":25,"title":["Full-length dystrophin deficiency leads to contractile and calcium transient defects in human engineered heart tissues"],"prefix":"10.1177","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3465-0442","authenticated-orcid":false,"given":"Samantha B","family":"Bremner","sequence":"first","affiliation":[{"name":"Department of Bioengineering, University of Washington, Seattle, WA, USA"},{"name":"Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian J","family":"Mandrycky","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Washington, Seattle, WA, USA"},{"name":"Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Leonard","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA"},{"name":"Department of Mechanical Engineering, University of Washington, Seattle, WA, USA"},{"name":"Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9693-446X","authenticated-orcid":false,"given":"Ruby M","family":"Padgett","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA"},{"name":"Department of Mechanical Engineering, University of Washington, Seattle, WA, USA"},{"name":"Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan R","family":"Levinson","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan S","family":"Rehn","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0179-3033","authenticated-orcid":false,"given":"J Manuel","family":"Pioner","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Florence, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan J","family":"Sniadecki","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Washington, Seattle, WA, USA"},{"name":"Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA"},{"name":"Department of Mechanical Engineering, University of Washington, Seattle, WA, USA"},{"name":"Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA"},{"name":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L","family":"Mack","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Washington, Seattle, WA, USA"},{"name":"Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA"},{"name":"Department of Rehabilitation Medicine, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2022,8,17]]},"reference":[{"key":"bibr1-20417314221119628","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-8966(02)00140-2"},{"key":"bibr2-20417314221119628","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.150.5.1209"},{"key":"bibr3-20417314221119628","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.2006.087643"},{"key":"bibr4-20417314221119628","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2009.06.002"},{"key":"bibr5-20417314221119628","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2003.09.005"},{"key":"bibr6-20417314221119628","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.17.9142"},{"key":"bibr7-20417314221119628","doi-asserted-by":"publisher","DOI":"10.1002\/jemt.1172"},{"key":"bibr8-20417314221119628","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2007.05.015"},{"key":"bibr9-20417314221119628","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds415"},{"key":"bibr10-20417314221119628","doi-asserted-by":"publisher","DOI":"10.3390\/molecules20058823"},{"key":"bibr11-20417314221119628","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2013.05.001"},{"key":"bibr12-20417314221119628","doi-asserted-by":"publisher","DOI":"10.1016\/0165-3806(95)00169-7"},{"key":"bibr13-20417314221119628","doi-asserted-by":"publisher","DOI":"10.1016\/0960-8966(94)90081-7"},{"key":"bibr14-20417314221119628","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2012.01630.x"},{"key":"bibr15-20417314221119628","volume":"4","author":"G\u00f3recki 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