Activating a patient-relevant pathogenic variant of a genetically defined heart disease in a humanized pig model
Abstract Complex diseases such as progressive cardiomyopathies are often insufficiently recapitulated in small animals or in vitro models. Large animal species such as pigs provide a valuable alternative, but constitutive genetic manipulation has not yet been applied to pigs in an effective manner, mainly due to biological and logistical limitations. Here we describe the generation of a humanized pig model for phospholamban-mediated cardiomyopathy and compare different methods for activating a pathogenic R14del mutation by Cre-mediated recombination. Both Cre treatment of pig primary cells before somatic cell nuclear transfer as well as microinjection of Cre-encoding mRNA into zygotes were similarly efficient in delivering piglets with an activated R14del mutation. Alternatively, administration of Cre-encoding adeno-associated virus into piglets was sufficient, albeit to a varying extent. Together, we describe a highly effective process to establish complex inducible genetic traits in pig and demonstrate that the lack of Cre-driver lines can be compensated by various interventions during reproduction or postnatally.
Authors
- Joost P. G. Sluijter (ORCID: https://orcid.org/0000-0003-2088-9102)
- Tarik Bozoglu (ORCID: https://orcid.org/0000-0002-6545-2150)
- Susanne Zöls
- Jana Juhásová (ORCID: https://orcid.org/0000-0001-7022-6812)
- Tatjana Dorn
- Mayuko Kurome (ORCID: https://orcid.org/0000-0002-2725-8613)
- Eckhard Wolf (ORCID: https://orcid.org/0000-0002-0430-9510)
- Andrea Bähr (ORCID: https://orcid.org/0000-0001-8075-8222)
- Nikolai Klymiuk (ORCID: https://orcid.org/0000-0003-3532-1659)
- Steffanie Senf (ORCID: https://orcid.org/0000-0002-4463-078X)
- Tuna Güngör
- Pieter C. Glijnis
- Zdeňka Ellederová (ORCID: https://orcid.org/0000-0001-6695-6345)
- Josep M. Cambra (ORCID: https://orcid.org/0000-0003-2010-5849)
- Christian Kupatt (ORCID: https://orcid.org/0000-0002-3611-1218)
- Mathias Ritzmann (ORCID: https://orcid.org/0000-0001-9791-1668)
- Michaela Vaškovičová (ORCID: https://orcid.org/0000-0003-4928-5732)
- Dávid Drutovič (ORCID: https://orcid.org/0000-0001-7099-3042)
- Štefan Juhás (ORCID: https://orcid.org/0000-0002-2866-0727)
- Valeri Zakhartchenko (ORCID: https://orcid.org/0000-0002-5974-9759)
- Pieter A. Doevendans (ORCID: https://orcid.org/0000-0002-6257-7169)
- Francesca Stillitano (ORCID: https://orcid.org/0000-0003-1898-5058)
- Petra Vochozková (ORCID: https://orcid.org/0000-0003-3691-0340)
- Vijayanand Rajendran (ORCID: https://orcid.org/0000-0002-6583-4044)
- J. Peter van Tintelen (ORCID: https://orcid.org/0000-0003-3854-6749)
- Magdaléna Harakaľová (ORCID: https://orcid.org/0000-0002-7293-1029)
- Motlik Jan
- Eva-Maria Männer
- Barbara Kessler
- Carolina G. Cabrera-Gomez
- Ina M. Luksch (ORCID: https://orcid.org/0009-0007-2708-2295)
- Mara L. Corsten
- Solomon K. Yator (ORCID: https://orcid.org/0009-0001-3303-6048)
- Heinke C. Heymer
- Jessica K. Hernandez
Institutions
- Utrecht University (NL)
- TUM Klinikum (DE)
- University Medical Center Utrecht (NL)
- Institute of Bioinformatics and Systems Biology (DE)
- Czech Academy of Sciences, Institute of Animal Physiology and Genetics (CZ)
- International Human Frontier Science Program Organization (FR)
- Technical University of Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Lab Animal
- Published
- 2026-09-11
- DOI
- https://doi.org/10.1038/s41684-026-01787-6
- Primary Topic
- Pluripotent Stem Cells Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00