Engineered heart muscle allografts for heart repair in primates and humans

Ahmad-Fawad Jebran, Tim Seidler, Malte Tiburcy, Maria Daskalaki, Ingo Kutschka, Buntaro Fujita, Stephan Ensminger, Felix Bremmer, Amir Moussavi, Huaxiao Yang, Xulei Qin, Sophie Mißbach, Charis Drummer, Hassina Baraki, Susann Boretius, Christopher Hasenauer, Tobias Nette, Johannes Kowallick, Christian O. Ritter, Joachim Lotz, Michael Didié, Mathias Mietsch, Tim Meyer, George Kensah, Dennis Krüger, Md Sadman Sakib, Lalit Kaurani, Andre Fischer, Ralf Dressel, Ignacio Rodriguez-Polo, Michael Stauske, Sebastian Diecke, Kerstin Maetz-Rensing, Eva Gruber-Dujardin, Martina Bleyer, Beatrix Petersen, Christian Roos, Liye Zhang, Lutz Walter, Silke Kaulfuß, Gökhan Yigit, Bernd Wollnik, Elif Levent, Berit Roshani, Christiane Stahl-Henning, Philipp Ströbel, Tobias Legler, Joachim Riggert, Kristian Hellenkamp, Jens-Uwe Voigt, Gerd Hasenfuß, Rabea Hinkel, Joseph C. Wu, Rüdiger Behr and Wolfram-Hubertus Zimmermann ()
Additional contact information
Ahmad-Fawad Jebran: University Medical Center Göttingen
Tim Seidler: Partner Site Lower Saxony
Malte Tiburcy: Partner Site Lower Saxony
Maria Daskalaki: Partner Site Lower Saxony
Ingo Kutschka: University Medical Center Göttingen
Buntaro Fujita: Campus Lübeck
Stephan Ensminger: Campus Lübeck
Felix Bremmer: Partner Site Lower Saxony
Amir Moussavi: Partner Site Lower Saxony
Huaxiao Yang: Stanford University School of Medicine
Xulei Qin: Stanford University School of Medicine
Sophie Mißbach: Partner Site Lower Saxony
Charis Drummer: Partner Site Lower Saxony
Hassina Baraki: University Medical Center Göttingen
Susann Boretius: Partner Site Lower Saxony
Christopher Hasenauer: University Medical Center Göttingen
Tobias Nette: University Medical Center Göttingen
Johannes Kowallick: Partner Site Lower Saxony
Christian O. Ritter: Partner Site Lower Saxony
Joachim Lotz: Partner Site Lower Saxony
Michael Didié: Partner Site Lower Saxony
Mathias Mietsch: Partner Site Lower Saxony
Tim Meyer: Partner Site Lower Saxony
George Kensah: University Medical Center Göttingen
Dennis Krüger: German Center for Neurodegenerative Diseases (DZNE)
Md Sadman Sakib: German Center for Neurodegenerative Diseases (DZNE)
Lalit Kaurani: German Center for Neurodegenerative Diseases (DZNE)
Andre Fischer: Partner Site Lower Saxony
Ralf Dressel: Partner Site Lower Saxony
Ignacio Rodriguez-Polo: Partner Site Lower Saxony
Michael Stauske: Partner Site Lower Saxony
Sebastian Diecke: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Kerstin Maetz-Rensing: German Primate Center–Leibniz Institute for Primate Research
Eva Gruber-Dujardin: German Primate Center–Leibniz Institute for Primate Research
Martina Bleyer: German Primate Center–Leibniz Institute for Primate Research
Beatrix Petersen: Partner Site Lower Saxony
Christian Roos: German Primate Center–Leibniz Institute for Primate Research
Liye Zhang: German Primate Center–Leibniz Institute for Primate Research
Lutz Walter: Partner Site Lower Saxony
Silke Kaulfuß: University Medical Center Göttingen
Gökhan Yigit: Partner Site Lower Saxony
Bernd Wollnik: Partner Site Lower Saxony
Elif Levent: Partner Site Lower Saxony
Berit Roshani: German Primate Center–Leibniz Institute for Primate Research
Christiane Stahl-Henning: German Primate Center–Leibniz Institute for Primate Research
Philipp Ströbel: University Medical Center Göttingen
Tobias Legler: Partner Site Lower Saxony
Joachim Riggert: Partner Site Lower Saxony
Kristian Hellenkamp: University Medical Center Göttingen
Jens-Uwe Voigt: University Hospitals Leuven
Gerd Hasenfuß: Partner Site Lower Saxony
Rabea Hinkel: Partner Site Lower Saxony
Joseph C. Wu: Stanford University School of Medicine
Rüdiger Behr: Partner Site Lower Saxony
Wolfram-Hubertus Zimmermann: Partner Site Lower Saxony

Nature, 2025, vol. 639, issue 8054, 503-511

Abstract: Abstract Cardiomyocytes can be implanted to remuscularize the failing heart1–7. 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.

Date: 2025
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DOI: 10.1038/s41586-024-08463-0

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