Engineered heart muscle allografts for heart repair in primates and humans
Ahmad-Fawad Jebran, Tim Seidler, Malte Tiburcy, Maria Anastasia 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 T. Kowallick, Christian Ritter, Joachim Lotz, Michael Didié, Matthias Mietsch, Tim Meyer, George Kensah, D. Krüger, M. Sadman Sakib, Lalit Kaurani, André Fischer, Ralf Dressel, Ignacio Rodríguez-Polo, Michael Stauske, Sebastian Diecke, Kerstin Maetz-Rensing, Eva Gruber-Dujardin, Martina Bleyer, Beatrix Petersen, Christian Roos, Liye Zhang, Lutz Walter, Silke Kaulfuß, Gökhan Yiğit, Bernd Wollnik, Elif Levent, Berit Roshani, Christiane Stahl‐Henning, Philipp Ströbel, Tobias J. Legler, J. Riggert, Kristian Hellenkamp, Jens‐Uwe Voigt, Gerd Hasenfuß, Rabea Hinkel, Joseph C. Wu, Rüdiger Behr, Wolfram‐Hubertus Zimmermann
Abstract
Abstract Cardiomyocytes can be implanted to remuscularize the failing heart 1–7 . 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 formulation 8 , 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.