{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T16:11:11Z","timestamp":1788883871637,"version":"build-2803163510"},"reference-count":45,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100007263","name":"Astellas Foundation for Research on Metabolic Disorders","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007263","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008667","name":"SENSHIN Medical Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008667","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["aiche.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Bioengineering &amp; Transla Med"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Dilated cardiomyopathy (DCM) is the most prevalent pediatric cardiomyopathy and has a poor prognosis. Although heart transplantation is the only curative option, the severe donor shortage in Japan underscores an urgent need for alternative therapies. Here, we generated induced pluripotent stem cell (iPSC) lines from two unrelated children with the same TNNT2\u2010R151W mutation. We then investigated the cellular characteristics of the cardiomyocytes derived from these iPSC lines (R151W iPSC\u2010CMs) and evaluated their contractile function in pillar\u2010based engineered heart tissue (EHT). We also assessed the therapeutic potential of overexpressing wild\u2010type TNNT2 in patient\u2010derived iPSCs (wtTNNT2\u2010OE\u2010iPSCs). R151W\u2010iPSC\u2010CMs exhibited pronounced sarcomere disarray, attenuated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transient amplitude, prolonged time to peak, and delayed decay tau. These characteristics are indicative of failing myocardium and were restored in wtTNNT2\u2010OE\u2010iPSC\u2010CMs. Pillar\u2010based EHT assays revealed a substantial decrease in contractile force in R151W\u2010EHTs compared to wtTNNT2\u2010OE\u2010EHTs, which is suggestive of the systolic dysfunction observed clinically in DCM. Collectively, these results provide the first functional evidence that the TNNT2\u2010R151W mutation leads to pediatric DCM by causing sarcomere insufficiency and disturbances in Ca\n                    <jats:sup>2+<\/jats:sup>\n                    handling. Our patient\u2010specific iPSC\u2010EHT platform faithfully recapitulates key features of pediatric DCM and could offer a robust system for mechanistic studies and drug testing. Furthermore, phenotypic rescue upon overexpression of wild\u2010type TNNT2 suggests that this allele is amenable to a gene replacement approach aimed at restoring wild\u2010type function in TNNT2\u2010mutant cardiomyopathies.\n                  <\/jats:p>","DOI":"10.1002\/btm2.70108","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T05:37:55Z","timestamp":1767764275000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Pediatric dilated cardiomyopathy caused by\n                    <scp>TNNT2<\/scp>\n                    \u2010\n                    <scp>R151W<\/scp>\n                    mutation: Modeling and rescue in patient\u2010derived\n                    <scp>i<\/scp>\n                    nduced pluripotent stem cells and engineered heart tissue"],"prefix":"10.1002","volume":"11","author":[{"given":"Toshiaki","family":"Nagashima","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery The University of Osaka Graduate School of Medicine  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7901-6133","authenticated-orcid":false,"given":"Kenji","family":"Miki","sequence":"additional","affiliation":[{"name":"Premium Research Institute for Human Metaverse Medicine, The University of Osaka  Osaka Japan"},{"name":"Institute for Protein Research, The University of Osaka  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaru","family":"Tsuchida","sequence":"additional","affiliation":[{"name":"Media Information Research Department NTT Communication Science Laboratories  Kanagawa 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