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Previous studies have demonstrated that BAG3 mediates sarcomeric protein turnover through chaperone-assisted selective autophagy to maintain sarcomere integrity in the human heart. Although mouse models provide valuable insights into whole-organism effects of BAG3 knockout or pathogenic variants, their utility is limited by species-specific differences in pathophysiology, which often do not translate to humans and contribute to the failure of clinical trials. As a result, the development of induced pluripotent stem cell-derived cardiomyocytes (iCM) and engineered heart tissues presents a promising alternative for studying adult-onset cardiac diseases. Here, we used genome engineering to generate an isogenic pseudo-wild-type control cell line from a patient-derived iPSC line carrying a pathogenic BAG3 variant, clinically presenting with DCM. While monolayer iCMs recapitulated some features of BAG3-mediated DCM, such as reduced autophagy, mitochondrial membrane potential, and decreased HSPB8 stability, they failed to develop the age-associated impairment in sarcomere integrity. Therefore, we developed a mature, patient-specific, human engineered heart tissue model of BAG3-mediated DCM and compared it to its isogenic healthy control. We demonstrated successful recapitulation of adult-like features of the clinically observed disorganized sarcomeres and impaired tissue contractility, thereby providing a platform to investigate BAG3-related pathophysiology and therapeutic interventions.<\/jats:p>","DOI":"10.1177\/20417314251371296","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T10:50:16Z","timestamp":1758538216000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":3,"title":["A patient-specific engineered tissue model of BAG3-mediated cardiomyopathy"],"prefix":"10.1177","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5511-6105","authenticated-orcid":false,"given":"Margaretha A. 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Advanced maturation of human cardiac tissue grown from pluripotent stem cells. 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