Organ transplantation is a key treatment for end-stage organ failure, but has long been limited by a shortage of donors. To solve this problem, scientists began exploring the possibility of transplanting organs from other species into the human body as early as the last century, and after many attempts and screenings, pigs were finally selected as the most ideal allogeneic donor. This choice was based on multiple considerations: the pig's organs are relatively close to those of humans in terms of size, structure, and physiological function, while being relatively inexpensive and less ethically controversial than those of primates.

With the rapid development of gene editing technology, the theoretical and technical barriers to xenotransplantation have gradually been broken down. Nowadays, scientists are able to accurately edit pig genes, knocking out key genes such as glycoprotein α-galactosyltransferase 1 (GGTA1) and cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) that trigger hyper-acute rejection, and at the same time, introducing human genes such as human thrombomodulin (hTBM) and hemoglobin oxygenase 1, which can significantly improve the compatibility of transplantation. These advances have laid a solid theoretical and technical foundation for the application of porcine organs in human transplantation.

In recent years, xenotransplantation research has made remarkable breakthroughs in preclinical and clinical stages. For example:

- In September 2021, porcine kidneys knocked out of the GGTA1 gene were transplanted into brain-dead recipients for the first time at New York University Langone Medical Center in the United States;

- In January 2022, the University of Maryland Medical Center completed the world's first gene-edited porcine heart transplantation into a living patient, who survived for 60 days after surgery;

- In March 2024, Massachusetts General Hospital successfully transplanted a multi-gene-edited porcine kidney into a living patient, who survived for two months after surgery.

These milestones have attracted widespread attention worldwide, further highlighting the enormous potential of xenotransplantation. However, due to the complexity of liver function, direct transplantation of porcine livers to living humans had not been realized prior to this.

On March 26, 2025, a team of Chinese researchers published a research paper entitled “Gene-modified pig-to-human liver xenotransplantation” in Nature, which appeared on the front page of Nature and attracted widespread attention in the academic community and society. The results have attracted widespread attention in the academic community and society.

In this study, gene-edited porcine livers were transplanted into brain-dead recipients by means of xenotopic-assisted transplantation, and the function and hemodynamics of the grafts, as well as the immune and inflammatory responses of the recipients, were systematically monitored within 10 days. The results showed that the transplanted porcine livers were able to produce bile and secrete albumin, and their liver function indexes were generally stable, hemodynamics were maintained normal, and there was no obvious rejection, and the immune and inflammatory responses were effectively controlled.

The research team also evaluated the gene-edited pigs and confirmed that the relevant genetic modifications achieved the expected results. This study preliminarily verifies the feasibility of pig-to-human liver xenotransplantation, and provides an important reference and practical basis for future liver transplantation.

Evaluation of gene-edited pigs

A six-gene-modified Parma miniature pig was used as the donor for the study. After gene editing, detection by flow cytometry, protein immunoblotting and immunohistochemical staining showed that most of the key genes triggering hyperacute rejection - GGTA1, B4GALNT2 and CMAH - were inactivated; while human complement regulatory proteins CD46 and CD55 were significantly overexpressed, and at the same time, the human Thrombomodulin gene hTBM. In addition, the level of xenoreactive immunoglobulin M and G antibodies was low in the recipients, and no porcine endogenous retrovirus, porcine cytomegalovirus infection or microchimerism was detected.

Fig. 1 Donor gene editing and pathogenicity monitoring

Heterotopic-assisted liver transplantation

Preoperative vascularization of the donor pig revealed that the size of its portal vein and inferior vena cava matched that of the recipient. The procedure was performed using an allograft-assisted transplantation method, in which the recipient inferior vena cava was partially excised, the superior vena cava of the donor liver was connected to the proximal part of the recipient's inferior vena cava, the donor portal vein was anastomosed to the distal part of the recipient's inferior vena cava, the donor hepatic artery was connected to the recipient's abdominal aorta, and the bile was drained out. The porcine liver was removed at the end of the study, and the recipient inferior vena cava was reconstructed with an artificial vessel (this procedure was performed on March 10, 2024).

Fig. 2 Heterotopic adjuvant liver xenografts

Functional performance of porcine liver

After transplantation, porcine livers began to produce golden-colored bile 2 hours after portal vein reperfusion, and both bile volume and porcine-derived albumin content increased after surgery, indicating that the liver could survive and function in the human body. Changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, which reflect liver function, were inconsistent, with ALT being normal and AST decreasing rapidly after being elevated postoperatively, but this did not necessarily mean that the grafts were functioning abnormally. In addition, alkaline phosphatase levels were normal, and bilirubin and gamma-glutamyl transpeptidase (gamma-GGT) were elevated later in life.

Fig. 3 Functions of xenografts

Hemodynamics after transplantation

Blood flow velocities in the porcine hepatic artery, portal vein and hepatic vein were found to be in the acceptable range postoperatively by ultrasound monitoring, and portal flow was stable. Although the platelet count decreased and the activated partial thromboplastin time (APTT) increased in the early postoperative period, they eventually returned to normal, and the prothrombin time (PT) was always maintained within the physiological range, indicating that the hTBM transgene effectively maintained circulatory homeostasis.

Fig. 4 Hemodynamic monitoring of xenografts

Histologic analysis of porcine liver

Multiple histologic tests of the donor liver revealed only mild sinusoidal congestion and inflammatory cell infiltration in the perioperative period, with no signs of immune rejection. The recipient's original liver tissue showed mild intrahepatic cholestasis at 10 days postoperatively, which may have been responsible for the late elevation of bilirubin and γ-GGT. The transplanted liver had a high proliferative capacity of hepatocytes, low stellate cell activation, good repopulation of hepatic sinusoidal endothelial cells (LSEC), and undamaged microstructure, and no viral particles were observed.

Fig. 5 Histology of xenograft liver and native human liver

Xenograft-induced immune response

The excessive immune response triggered by xenografts was suppressed using several immunosuppressive agents, including methylprednisolone, tacrolimus, and mycophenolate mofetil. Biopsy of the grafts revealed low complement C3d, C4d, and C5b-9 deposition, and moderate amounts of IgM and IgG were detected in the grafts at 10 days postoperatively, but there were no significant perioperative changes in serum IgM and IgG levels. Postoperative T cells were suppressed by anti-thymocyte globulin, B cells were first elevated and then suppressed by rituximab, levels of inflammatory response-associated C-reactive protein and calcitoninogen were first elevated and then decreased, and other cytokines were effectively controlled, indicating that the inflammatory response was well controlled after transplantation.

Fig. 6 Immune and inflammatory monitoring of receptors

The research team preliminarily determined the feasibility and related mechanisms of genetically modified porcine liver in human applications. The study successfully transplanted six gene-edited porcine livers into brain-dead recipients in an ectopic-assisted manner, and the grafts performed well functionally, with hemodynamic stability and effective control of immune and inflammatory responses during the 10-day monitoring period. This confirms the potential and safety of gene-edited porcine liver for human application, and provides a valuable practical basis for subsequent research.

The allogeneic-assisted transplantation approach used in this study demonstrates the potential as a transitional treatment for patients with liver failure. However, it should be noted that the “allograft-assisted transplantation” approach does not remove the recipient's original liver, but instead places the porcine liver in the abdominal cavity. Because the recipient retains his or her own liver, it is not yet possible to fully confirm whether it will provide adequate physiologic function when the patient is completely dependent on the allogeneic liver. Nonetheless, this trial has gained important experience for future in situ transplantation and has far-reaching significance in pioneering the field of xenotransplantation.

Excitingly, on January 11 this year, the team made a further breakthrough by successfully implanting a gene-edited porcine liver in situ into a brain-dead patient, realizing for the first time in the international arena the complete substitution of a human liver by a xenogeneic liver. When the blood flow of the transplanted porcine liver was opened during the operation, the patient's organs had good blood perfusion and rapidly produced bile. On the day after the operation, the patient's vital signs were stable and many indicators such as liver function gradually recovered.

Reference:Gene-modified pig-to-human liver xenotransplantation | Nature