Engineered heart muscle allografts for heart repair in primates and humans

• 成果类型: Article
• 署名作者: Jebran, Ahmad-Fawad; Seidler, Tim; Tiburcy, Malte; Daskalaki, Maria; Kutschka, Ingo; Fujita, Buntaro; Ensminger, Stephan; Bremmer, Felix; Moussavi, Amir; Yang, Huaxiao; Qin, Xulei; Missbach, Sophie; Drummer, Charis; Baraki, Hassina; Boretius, Susann; Hasenauer, Christopher; Nette, Tobias; Kowallick, Johannes; Ritter, Christian O.; Lotz, Joachim; Didie, Michael; Mietsch, Mathias; Meyer, Tim; Kensah, George; Krueger, Dennis; Sakib, Md Sadman; Kaurani, Lalit; Fischer, Andre; Dressel, Ralf; Rodriguez-Polo, Ignacio; Stauske, Michael; Diecke, Sebastian; Maetz-Rensing, Kerstin; Gruber-Dujardin, Eva; Bleyer, Martina; Petersen, Beatrix; Roos, Christian; Zhang, Liye; Walter, Lutz; Kaulfuss, Silke; Yigit, Goekhan; Wollnik, Bernd; Levent, Elif; Roshani, Berit; Stahl-Henning, Christiane; Stroebel, Philipp; Legler, Tobias; Riggert, Joachim; Hellenkamp, Kristian; Voigt, Jens-Uwe; Hasenfuss, Gerd; Hinkel, Rabea; Wu, Joseph C.; Behr, Ruediger; Zimmermann, Wolfram-Hubertus
• 署名单位: University of Gottingen; UNIVERSITY GOTTINGEN HOSPITAL; German Centre for Cardiovascular Research; University of Gottingen; UNIVERSITY GOTTINGEN HOSPITAL; Justus Liebig University Giessen; University of Gottingen; UNIVERSITY GOTTINGEN HOSPITAL; Leibniz Association; Deutsches Primatenzentrum (DPZ); University of Kiel; Schleswig Holstein University Hospital; German Centre for Cardiovascular Research; University of Gottingen; UNIVERSITY GOTTINGEN HOSPITAL; Leibniz Association; Deutsches Primatenzentrum (DPZ); Stanford University; Stanford University; Leibniz Association; Deutsches Primatenzentrum (DPZ); University of Gottingen; UNIVERSITY GOTTINGEN HOSPITAL; Helmholtz Association; German Center for Neurodegenerative Diseases (DZNE); University of Gottingen; UNIVERSITY GOTTINGEN HOSPITAL; University of Gottingen; University of Gottingen; UNIVERSITY GOTTINGEN HOSPITAL; Helmholtz Association; Max Delbruck Center for Molecular Medicine; German Centre for Cardiovascular Research; Leibniz Association; Deutsches Primatenzentrum (DPZ); Leibniz Association; Deutsches Primatenzentrum (DPZ); University of Gottingen; UNIVERSITY GOTTINGEN HOSPITAL; Leibniz Association; Deutsches Primatenzentrum (DPZ); University of Gottingen; UNIVERSITY GOTTINGEN HOSPITAL; KU Leuven; KU Leuven; University Hospital Leuven; Helmholtz Association; German Center for Neurodegenerative Diseases (DZNE)
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2194
• DOI: 10.1038/s41586-024-08463-0
• 发表日期: 2025-03-13
• 关键词: cell-derived cardiomyocytes; pluripotent stem-cells; myocardial-infarction; long-term; transplantation; tissue; arrhythmias; prevention; survival

摘要

Cardiomyocytes can be implanted to remuscularize the failing heart1, 2, 3, 4, 5, 6-7. Challenges include sufficient cardiomyocyte retention for a sustainable therapeutic impact without intolerable side effects, such as arrhythmia and tumour growth. We investigated the hypothesis that epicardial engineered heart muscle (EHM) allografts from induced pluripotent stem cell-derived cardiomyocytes and stromal cells structurally and functionally remuscularize the chronically failing heart without limiting side effects in rhesus macaques. After confirmation of in vitro and in vivo (nude rat model) equivalence of the newly developed rhesus macaque EHM model with a previously established Good Manufacturing Practice-compatible human EHM formulation8, long-term retention (up to 6 months) and dose-dependent enhancement of the target heart wall by EHM grafts constructed from 40 to 200 million cardiomyocytes/stromal cells were demonstrated in macaques with and without myocardial infarction-induced heart failure. In the heart failure model, evidence for EHM allograft-enhanced target heart wall contractility and ejection fraction, which are measures for local and global heart support, was obtained. Histopathological and gadolinium-based perfusion magnetic resonance imaging analyses confirmed cell retention and functional vascularization. Arrhythmia and tumour growth were not observed. The obtained feasibility, safety and efficacy data provided the pivotal underpinnings for the approval of a first-in-human clinical trial on tissue-engineered heart repair. Our clinical data confirmed remuscularization by EHM implantation in a patient with advanced heart failure.