Engineered heart muscle allografts for heart repair in primates and humans
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.
Article Details
Authors (55)
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
Wolfram-Hubertus Zimmermann