Wolf Lab - Research

Xenotransplantation

The shortage of human donor organs has accelerated research into xenotransplantation, using genetically modified pigs as donors of organs, tissues, and cells, and exogenesis, the generation of humanized organs in animals (Fig. 1). Advances in genetic engineering have significantly reduced immunological barriers to xenotransplantation, bringing clinical applications closer to reality (1–4).

Fig. 1. From Gene-Editing to Exogenesis: Pigs as a Source of Immune-Compatible Organs for Transplantation (from Ref. 7; created with BioRender.com).

Genetically Modified Pigs for Organ Transplantation

Our research focuses on developing genetically modified donor pigs with improved immunological compatibility and suitable organ dimensions.
Auckland Island pigs are particularly promising due to their relatively small body size, normal cardiac function, and distinctive genetic characteristics, including homozygosity of the swine leukocyte antigen (SLA) locus (5).
To overcome immune rejection and coagulation incompatibilities, we engineer pigs with:

• Elimination of major carbohydrate xenoantigens (α-Gal, Neu5Gc, Sda) through targeted gene knockouts.
• Expression of human CD46 to regulate complement activation.
• Expression of human thrombomodulin (hTHBD) to improve coagulation compatibility.

Our triple-genetically modified pigs consistently express human CD46 and thrombomodulin while lacking α-Gal. Their hearts supported baboon survival for two months following orthotopic transplantation without evidence of rejection or complement activation.
Future work combines additional genetic modifications, including CD47 and HLA-G expression, to further improve immune compatibility. We also investigate exogenesis, aiming to generate pig organs with fully humanized cellular compartments, such as vascular endothelium (6, 7).

Porcine Islet Xenotransplantation for Diabetes

A second major research focus is the development of genetically modified neonatal porcine islets (NPIs) for β-cell replacement therapy in diabetes (Fig. 2). Porcine islets could provide a scalable alternative to scarce human donor islets and potentially reduce the need for lifelong immunosuppression (8, 9).

Fig. 2. Potential barriers and strategies to counter them in β-cell replacement therapy (from Ref. 8; created with BioRender.com).

We have developed donor pigs expressing immune-protective factors, including LEA29Y, human PD-L1, and human CD47, alongside targeted inactivation of CCL2. These modifications address adaptive and innate immune responses. Notably, LEA29Y-expressing porcine islets demonstrated long-term graft function without systemic immunosuppression in preclinical models (10).
Our research also advances islet culture, maturation, and quality assessment through molecular profiling, single-cell transcriptomics, and multi-omics approaches. Additionally, Exendin-4 PET/CT imaging enables non-invasive monitoring of transplanted islets in a genetically diabetic pig model (11).
Through interdisciplinary collaborations, we are developing strategies to improve graft survival, function, and clinical applicability (12).

Future Perspectives

Our goal is to advance genetically modified porcine organs and islets toward safe and effective clinical transplantation. Current priorities include optimizing immune-protective genetic modifications, developing humanized organs through exogenesis, and establishing robust manufacturing, quality-control, and regulatory frameworks for clinical translation.

Funding

German Research Foundation (DFG; SFB-TR 127) | Swiss National Science Foundation (Sinergia project “Xeno2Cure – advanced engineering and testing of organ donor pigs”) | Leducq Foundation (23CVD01) | German Center for Diabetes Research (DZD; 82DZD00802, 82DZD08E1G, 82DZD08G1G) | European Union (H2020 iNanoBIT) | Breakthrough T1D (subcontract partner of 3-SRA-2022-1155-S-B, 3-SRA-2023-1420-S-B, 3-SRA-2026-1808-S-B).

Selected Publications

1. Ali A, Kemter E, Wolf E. Advances in Organ and Tissue Xenotransplantation. Annu Rev Anim Biosci. 2024;12:369–390. https://doi.org/10.1146/annurev-animal-021122-102606
2. Ali A, Kurome M, Kessler B, Kemter E, Wolf E. What Genetic Modifications of Source Pigs Are Essential and Sufficient for Cell, Tissue, and Organ Xenotransplantation? Transpl Int. 2024;37:13681. https://doi.org/10.3389/ti.2024.13681
3. Längin M, et al. Consistent success in life-supporting porcine cardiac xenotransplantation. Nature. 2018;564:430–433. https://doi.org/10.1038/s41586-018-0765-z
4. Reichart B, et al. Cardiac xenotransplantation: from concept to clinic. Cardiovasc Res. 2023;118:3499–3516. https://doi.org/10.1093/cvr/cvac180
5. Lange A, et al. Genetic diversity, growth and heart function of Auckland Island pigs, a potential source for organ xenotransplantation. Xenotransplantation. 2024;31. https://doi.org/10.1111/xen.12858
6. Garry DJ, Wolf E; XenExoCor consortium. Leducq-funded programme: engineering pig hearts for transplantation. Eur Heart J. 2025;46:2727–2729. https://doi.org/10.1093/eurheartj/ehaf270
7. Ali A, et al. From Gene Editing to Exogenesis: Pigs as a Source of Immune-compatible Organs for Transplantation. Transplantation. 2026;110–e2006. https://doi.org/10.1097/TP.0000000000005845
8. Grimus S, et al. Immunoprotection Strategies in β-Cell Replacement Therapy: A Closer Look at Porcine Islet Xenotransplantation. Adv Sci. 2024;11. https://doi.org/10.1002/advs.202401385
9. Kemter E, Wolf E. Recent progress in porcine islet isolation, culture and engraftment strategies for xenotransplantation. Curr Opin Organ Transplant. 2018;23:633–641. https://doi.org/10.1097/MOT.0000000000000579
10. Seissler J, et al. Anti-CTLA-4 Treatment Abrogates Co-stimulation Blockade-induced Acceptance of Transgenic Porcine Islets in Humanized Mice. Transplantation. 2025;109–e696. https://doi.org/10.1097/TP.0000000000005512
11. Pilz J, et al. Functional maturation and longitudinal imaging of intraportal neonatal porcine islet grafts in genetically diabetic pigs. Am J Transplant. 2024;24:1395–1405. https://doi.org/10.1016/j.ajt.2024.02.026
Citro A, et al. Directed self-assembly of a xenogeneic vascularized endocrine pancreas for type 1 diabetes. Nat Commun. 2023;14:878. https://doi.org/10.1038/s41467-023-36582-1