Human iPSC-cardiomyocyte-aggregate cell therapy in non-human primates and correlation of heart recovery with contractile and electrophysiological cardiomyocyte properties
This study demonstrates the successful production and injection of human induced pluripotent stem cell cardiomyocyte aggregates into infarcted cynomolgus monkey hearts, resulting in substantial, structured human grafts three months after cell transplantation. Transient graft-induced arrhythmias decreased over time. Both the arrhythmogenicity and the substantial heart function recovery in vivo notably seemed to correlate with induced pluripotent stem cell clone-dependent contractile and electrophysiological cardiomyocyte properties in vitro. Overexpression of a red fluorescent reporter protein led to a dysregulated conduction and contraction machinery in yet engraftment competent cardiomyocytes, providing an important tool to mechanistically understand and improve induced pluripotent stem cell-based heart repair in preclinical models.We demonstrate the logistically important, temporal uncoupling of cardiomyocyte production from transplantation. Cardiomyocyte aggregate transplantation yielded results comparable to the reported transplantation of 10-20-fold higher numbers of dissociated human embryonic stem cell- cardiomyocytes and suggests a higher degree of cell/ tissue maturation in cardiac grafts. Our study promotes reduced cell production costs, highlights the need for an in vitro potency assay, and shows a pragmatic new avenue for the clinical translation of human induced pluripotent stem cell-based heart repair.
Authors
- Annette Schrod
- Alexandra Haase (ORCID: https://orcid.org/0000-0003-2666-4297)
- Veronika Fricke (ORCID: https://orcid.org/0000-0002-8933-8862)
- Nissim Benvenisty (ORCID: https://orcid.org/0000-0001-8234-2685)
- Morsi Arar
- Ina Gruh (ORCID: https://orcid.org/0000-0002-7756-0490)
- Tim Kohrn
- Nils Kriedemann (ORCID: https://orcid.org/0000-0001-7767-1556)
- Merlin Witte
- Serghei Cebotari
- Jonathan Jung (ORCID: https://orcid.org/0000-0002-3342-1245)
- Karen Lampe (ORCID: https://orcid.org/0000-0003-0096-9607)
- Robert Zweigerdt (ORCID: https://orcid.org/0000-0002-4656-0770)
- Vojtěch Hradil
- Martin Fischer (ORCID: https://orcid.org/0000-0002-3429-1876)
- Andreas Martens (ORCID: https://orcid.org/0000-0002-7953-2645)
- Stephan Hohmann (ORCID: https://orcid.org/0000-0002-1606-3423)
- Kühnel Mark
- Jana Teske (ORCID: https://orcid.org/0009-0000-4713-0900)
- Annika Franke
- Karlo Komorowski
- Danny Jonigk (ORCID: https://orcid.org/0000-0002-5251-2281)
- Susann Boretius (ORCID: https://orcid.org/0000-0003-2792-7423)
- Kerstin Mätz‐Rensing
- Amir Moussavi
- Tobias Goecke
- Klaus Hoeffler
- Wiebke Triebert
- Christopher Werlein (ORCID: https://orcid.org/0000-0002-7694-4257)
- David Duncker (ORCID: https://orcid.org/0000-0003-2996-6338)
- Mónika Szepes
- Caroline Halloin
- Jeanne de la Roche (ORCID: https://orcid.org/0000-0001-5753-1732)
- Ulrich Martin (ORCID: https://orcid.org/0000-0003-1058-4540)
- Anna-Lena de Vries
- Jörg Eiringhaus
- Kevin Cyrys
- Arjang Ruhparwar
- Christian Veltmann
- Anna Kuleshova
- Sara Szadocka
- Paul Frank
- Axel Haverich
Institutions
- Carl von Ossietzky Universität Oldenburg (DE)
- Hebrew University of Jerusalem (IL)
- German Primate Center (DE)
- Medizinische Hochschule Hannover (DE)
- German Center for Lung Research (DE)
- Foundation of Cardiac Surgery Development (PL)
- RWTH Aachen University (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-08-26
- DOI
- https://doi.org/10.1038/s41467-026-77103-0
- Primary Topic
- Pluripotent Stem Cells Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsches Zentrum für Herz-Kreislaufforschung
- Niedersächsische Ministerium für Wissenschaft und Kultur
- European Commission
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Deutsches Zentrum für Lungenforschung
- Horizon 2020 Framework Programme
- HORIZON EUROPE Framework Programme