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, Didié Michael, Mietsch Mathias, Meyer Tim, Kensah George, Krüger 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 Gökhan, Wollnik Bernd, Levent Elif, Roshani Berit, Stahl-Henning Christiane, Ströbel Philipp, Legler Tobias, Riggert Joachim, Hellenkamp Kristian, Voigt Jens-Uwe, Hasenfuß Gerd, Hinkel Rabea, Wu Joseph C, Behr Rüdiger, Zimmermann Wolfram-Hubertus
Department of Cardiothoracic and Vascular Surgery, University Medical Center Göttingen, Göttingen, Germany.
German Centre for Cardiovascular Research (DZHK), Partner Site Lower Saxony, Göttingen, Germany.
Nature. 2025 Mar;639(8054):503-511. doi: 10.1038/s41586-024-08463-0. Epub 2025 Jan 29.
Cardiomyocytes can be implanted to remuscularize the failing heart. 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, 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.
心肌细胞可被植入以恢复衰竭心脏的肌肉组织。挑战包括使心肌细胞充分留存以产生可持续的治疗效果，同时避免出现诸如心律失常和肿瘤生长等无法耐受的副作用。我们研究了以下假设：源自诱导多能干细胞的心肌细胞和基质细胞构建的心外膜工程心肌（EHM）同种异体移植物，可在不产生明显副作用的情况下，在结构和功能上使慢性衰竭的恒河猴心脏恢复肌肉组织。在确认新开发的恒河猴EHM模型在体外和体内（裸鼠模型）与先前建立的符合药品生产质量管理规范的人EHM制剂等效后，在有和没有心肌梗死诱导的心力衰竭的恒河猴中，均证明了由4000万至2亿个心肌细胞/基质细胞构建的EHM移植物可实现长期留存（长达6个月）并使靶心壁呈剂量依赖性增厚。在心力衰竭模型中，获得了EHM同种异体移植物增强靶心壁收缩力和射血分数的证据，这是局部和整体心脏支持的指标。组织病理学和基于钆的灌注磁共振成像分析证实了细胞留存和功能性血管化。未观察到心律失常和肿瘤生长。所获得的可行性、安全性和有效性数据为批准首例组织工程心脏修复人体临床试验提供了关键依据。我们的临床数据证实了在一名晚期心力衰竭患者中通过植入EHM实现了肌肉组织恢复。
