First Gene-Modified Pig Liver Xenotransplantation Into Human Recipient

Chinese researchers report successfully transplanting a gene-modified pig liver into a human recipient that integrated without signs of rejection, marking a significant milestone in addressing the critical shortage of liver organ donors. This breakthrough, published in Nature Medicine, follows a string of successful transplants that began in 2022. Surgeons in China and the United States transplanted hearts, kidneys, and a thymus gland from pigs into a handful of patients. Several recipients died within months—though it is unclear if that was primarily caused by the xenotransplantation—and others recovered well and were discharged from the hospital.

As to why the liver has lagged behind these other pig organ transplants, co-senior author Lin Wang from Xijing Hospital at the Fourth Military Medical University in Xi’an, China, explained, “Scientists all over the world, especially the scientists from the United States, have transplanted the kidney and the pig heart to human patients—so why is liver xenotransplantation so difficult? The function of the liver is so complicated. The heart’s main function is to pump blood to the whole human body, and the kidneys’ major function is to produce urine. However, the liver has many functions: producing bile, albumin, and factors to modulate the immune system.”

In 2013, Wang and his colleagues were the first in China to successfully transplant a pig liver into a monkey, which survived 14 days. Last year, Penn Medicine did the first successful external liver perfusion using a gene-edited pig liver. Blood in a brain-dead patient circulated through a pig’s liver that was outside the person’s body. Now, Wang and his colleagues from Fourth Military Medical University in Xi’an, China, attempted the first heterotopic auxiliary liver transplantation. Wang said that the heterotopic auxiliary approach was chosen because the key question was whether the pig liver could function at all when in a human body and not whether it could fully replace the original human liver. Of this work, Wang said, “It’s a great achievement because this is the first time we tried whether the pig liver could function well in the human body. Only then can there be a successful replacement of the original human liver in the future.”

The heterotopic auxiliary liver transplantation was officially performed on March 10, 2024, ​​three days after a 50-year-old adult recipient received a brain death diagnosis, maintained stable circulation, and had no underlying diseases. At the request of the recipient’s family, the study was artificially terminated 10 days after surgery (March 20, 2024). “The reason that we terminated the [investigation was at] the request of the family members,” said Wang. “Before the research and investigation, we had set quite a lot of agreements, especially…agreements by the major members of the patient’s family.” It is unclear from Wang’s comments as to what exactly then happened with the patient, who said, “After the investigation, the whole family took the brain-dead human back to their hometown.”

A safe but slow trickle

The donor’s liver came from a six-gene-modified Bama miniature pig provided by Clonorgan Biotechnology. The pig’s genetic modifications targeted three key genes—GGTA1, B4GALNT2, and CMAH—known to mediate hyperacute rejection. Additionally, human complement regulatory proteins CD46 and CD55, which protect against immune attacks, were overexpressed. The pig’s genome was further altered to include human thrombomodulin (hTBM) to prevent blood clot formation. Tests confirmed that porcine endogenous retroviruses and cytomegaloviruses were absent in both the donor pig and the recipient.

The pig liver was connected to the recipient’s vascular system while maintaining the recipient’s native liver. This intricate procedure involved precise vascular connections between the donor liver and the recipient’s inferior vena cava, portal vein, and abdominal aorta. Within hours of transplantation, the pig liver began producing bile and albumin—key indicators of liver function—albeit at levels far below those a healthy human liver produced. “To be frank, the [volume of] albumin and bile produced by the pig liver volume is not that great—it could not be comparable to the bile and the albumin produced by human beings,” said Wang. “The pig liver could produce pig-derived albumin, which just partially manifested…and functioned a little bit in a human being. So, currently, I cannot give you a definite answer as to whether pig livers could produce bile or albumin comparable to the human liver.”

Despite some fluctuations in liver enzymes, including a temporary rise in aspartate aminotransferase (AST), the researchers found no evidence of graft malfunction. Other liver function markers, such as alkaline phosphatase and bilirubin levels, largely remained within or near normal ranges. Continuous monitoring showed stable blood flow in the transplanted liver’s arteries and veins, confirming the re-establishment of its vascular system. While there were minor early changes in platelet levels and clotting times, these normalized as the recipient’s coagulation system adapted to the xenograft.

Detailed analyses revealed minimal immune-related changes in the transplanted liver. Microscopic evaluation showed that the liver’s microcirculation remained intact, with healthy cell regeneration and no signs of rejection or fibrogenesis. Electron microscopy confirmed the preservation of liver ultrastructure and the absence of viral particles. To prevent immune rejection, the recipient was administered a combination of immunosuppressants, including methylprednisolone, tacrolimus, and rituximab. While moderate immunoglobulin levels were detected in the xenograft, serum antibody levels remained stable. Proinflammatory cytokines, including interleukin-6 and tumor necrosis factor (TNF), were effectively suppressed, and the overall inflammatory response was well-managed.

A temporary bridge

The ability of a gene-modified pig liver to function in a human body for an extended period highlights the potential of xenotransplantation to address critical shortages for liver transplants. Wang said, “The heterotopic auxiliary liver transplantation may give us the bridge therapy opportunity for the future to solve the problem of the patient with severe liver failure. It is our dream to make this achievement. But we could not see whether the pig liver could support the patient with severe liver failure for a long time. We do not know the exact amount of time a pig liver could support a human body…because currently our investigation is just within 10 days. We will try to answer how long the pig liver could survive and support the human body in a future experiment.”

Regarding the future of pig liver xenotransplantations, Wang mentioned that a couple of months ago, the team tried to give a complete replacement of the original human liver replaced by a pig liver (but did not elaborate further). Although a complete liver replacement may be some time off, this research highlights the potential for pig livers to act as a “bridging organ” for patients awaiting a transplant or to sustain liver function while the organ regenerates. Nevertheless, further research is needed to optimize long-term graft survival and immune compatibility, whether for auxiliary heterotopic transplantations or full liver replacements.