September 7, 2023

expert reaction to humanized kidneys grown in pigs

A study published in Cell Stem Cell looks at the growth of humanized kidneys in pigs from stem cells. 

Dr Alena Pance, Senior Lecturer in Genetics, University of Hertfordshire, said:

“The authors quote previous work done in this area, but it is overall a new area of study in stem cell technology. This particular work indicates that it is possible to generate mesonephric tissue in complemented embryos, though the proportion of human contribution to this tissue is between 40 and 60%. This means that this is a chimera of human and pig cells, which will have implications on the potential applications expressed for this technology, i.e. transplantation.

“The concerning issue is that the human pluripotent stem cells are engineered to overexpress two genes, one is an oncogene that maintains proliferation potential and the other is a survival gene that essentially prevents the cells from dying. While expression of these genes helps the human cells to survive in the pig embryo and create mesonephroi structures, their long term expression and effects on the cells are not described (or at least not in the main text, which only states that it is an inducible system that is not turned on after implantation). This is important because the expression system used can be leaky and represent a hindrance to any clinical use of the biological material. In fact, it could be at least partly the reason for the high degeneration of the complemented embryos observed in the study and perhaps explain why out of 1820 embryos implanted only 5 normal ones were analysed.”

Prof Darius Widera, Professor of Stem Cell Biology and Regenerative Medicine, University of Reading, said:

“The study by Wang and colleagues describes the generation of mid-stage kidneys containing human cells in genetically modified pigs. The authors introduced a genetic mutation preventing the pigs from developing normal kidneys and supplemented the missing pig cells with human-induced pluripotent stem cells. This resulted in the development of mid-stage kidneys containing ~50% human cells.

“This experimental approach could pave the way for the development of new technologies allowing the growth of human organs in pigs. In the future, an optimised version of this technology could address the current shortage of compatible donors for kidney transplantation. This method can also be valuable for studying human diseases and conditions, potentially leading to better therapeutic options for patients.

“Although this approach is a clear milestone and the first successful attempt to grow whole organs containing human cells in pigs, the proportion of human cells in the generated kidneys is still not high enough. Human kidneys are complex organs composed of many different cell types. Until all of the cells are human, such organs could still be rejected by the recipient. Another challenge is the low efficiency of the method.

“Importantly, the authors found human cells in the pig brains, raising important ethical questions.”

Prof Dusko Ilic, Professor of Stem Cell Sciences, King’s College London, said:

“The paper describes pioneering steps in a new approach to organ bioengineering using pigs as incubators for growing and cultivating human organs. As the authors admitted, there are plenty of challenges. Will this approach prove to be the ultimate solution? Only time holds the answer.

“Nevertheless, this captivating strategy warrants further exploration. Undoubtedly, tackling the complexities of vasculature and innervation will pose the greatest technical hurdles, alongside the imperative task of preventing human cells from integrating into the animal’s brain.”

Quote provided by our colleagues at SMC Spain:

Rafael Matesanz, creator and founder of Spain’s National Transplant Organisation, says:

“The research group at the University of Canton [China] adds important advances in one of the avenues that has generated most interest over the last few years, within the long march of biomedical research to develop a model for the production of organs suitable for transplantation by using pigs as a vehicle animal—which already started in the last century.

“This research involves the creation of human-pig embryonic chimeras using pluripotent stem cells, so that the animals could serve as incubators for hypothetical customised organs created from the patient’s own cells, thereby avoiding the risk of rejection.

“Within this line of research, which has been developed over the last decade, the figure of [Spanish] scientist Juan Carlos Izpisúa, based in California, stands out, as well as that of Japanese researcher Hiromitsu Nakauchi. Izpisúa’s research has demonstrated the possibility of hybridisation between two apparently similar but genetically very different species—such as the mouse and the rat—achieving the development of mouse organs in rats, including the gall bladder that rats don’t have.

“Continuing along these lines, in 2017, in collaboration with the Catholic University of Murcia, Izpisúa published in Cell for the first time the creation of chimeric human embryos in large animals, specifically pigs. Implanted in female pigs, they could grow until they were three weeks old, given the legal impossibility in Spain to go beyond that date. No organs were formed, as the aim was simply to demonstrate that human cells could be integrated into a species far removed from humans.

“Already at that time, several serious problems were pointed out when it came to continuing the research. On the one hand, this technique had a low efficiency, with a little more than 1% of the implanted embryos being successful, a very low percentage for the intended purpose. On the other hand, in order to develop kidneys or other humanised organs inside pigs, it is necessary that the pigs do not develop their own, which requires specific manipulations with deletion of the responsible genes.

“Moreover, the creation of human-animal hybrids, beyond a certain stage, is subject to severe ethical and legal restrictions in most countries. In fact, in 2019, the same authors published in Nature the creation of human-monkey hybrid embryos, but moving the research to China (it wouldn’t have been possible in the USA or in Spain) and stopping the experiment at week 14— the moment when the development of the central nervous system begins, which implies a high level of risk. At the same time, Nakauchi, working between Tokyo and Stanford, obtained permission from the Japanese government to create hybrid embryos of human cells with animals, in this case rats, to implant them in these animals and carry the pregnancy to term.

“The current paper by the University of Canton group aims to find solutions to many of these obstacles. Carried out in China for the reasons outlined above, it is the first time that an entire human-pig chimeric organ has been created using the pig as an incubator.

“After the animals were sacrificed at 25-28 days, kidneys with a normal structure and 50-60% human cells were extracted, which is very promising indeed.

“To do this, they created a ‘niche’ in the pig embryo by CRISPR deletion of two genes on which kidney formation depends, so that human cells would not have to compete with porcine cells. They used specifically prepared human pluripotent cells and grew the embryos before implantation in special culture media.

“These measures greatly increased the efficiency of the procedure, which was one of the weaknesses of former experiments. In addition, the presence of human cells outside the ‘niche’ was found to be very limited. This is very important, because the invasion of reproductive tissues or the central nervous system, with the consequent risk of uncontrolled creation of human-pig hybrids, has been one of the main ethical problems of these procedures.

“The next steps will be to allow embryos to grow longer and to start doing the same with other organs and tissues, although the kidney is undoubtedly the most sought-after organ for transplantation. The authors themselves acknowledge that the clinical use of this technology is years away, but it is a major achievement on the road to unlimited organ production for transplantation.”

‘Generation of a humanized mesonephros in pigs from induced pluripotent stem cells via embryo complementation’ by Jiaowei Wang et al. was published in Cell Stem Cell at 4pm UK TIME on Thursday 7 September.

DOI: https://doi.org/10.1016/j.stem.2023.08.003

Declared interests

Darius Widera: “I have no conflict of interest to declare.”

Dusko Ilic: “I declare no interest.”

Rafael Matesanz does not declare any conflicts of interest.

No others received.