New hope for the shortage of donor organs! Chinese scientists regenerate human mid-term kidneys in pigs

On September 7, a research team from the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, published a cover article in the international academic journal Cell Stem Cell. The researchers used a new type of human induced pluripotent stem cells, combined with an optimized embryo compensation technology system, to achieve xenogeneic in vivo regeneration of humanized mesonephros in a kidney-deficient pig model. This is the first reported case of xenogeneic in vivo regeneration of a humanized functional organ in the world.

Organ transplantation has become the only effective treatment for many terminal diseases, but the severe shortage of donor organs limits the widespread clinical application of this therapy.

"Stem cell-based organ regeneration in xenogeneic animals will be an ideal way to solve this problem in the future." Lai Liangxue, a researcher at the Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences and one of the co-corresponding authors of the paper, introduced that the humanized organs obtained through this approach not only have a more comprehensive range of cell types and more complete organ structure and function, but also because the donor cells are derived from the patient's own body, they can effectively avoid problems such as immune rejection in xenogeneic organ or allogeneic organ transplantation.

However, there are many obstacles to achieving humanized organ xenogeneic regeneration based on embryo compensation technology. The insufficient differentiation ability of human pluripotent stem cells and their low survival ability in xenogeneic animal embryos, the difficulty in forming organ defect niches provided by large animal models, and the imperfect xenogeneic embryo chimeric compensation technology system have led to the failure of the idea of ​​cultivating human organs from pigs.

In order to seek a breakthrough, the research groups of Lai Liangxue, Pan Guangjin and Miguel A. Esteban from the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, formed a joint research team. With the support of the Chinese Academy of Sciences' strategic leading scientific project "Organ Reconstruction and Manufacturing", they have conducted more than five years of exploration around the world's difficult problem of xenogeneic regeneration of human kidneys.

The research team optimized the human-pig embryo compensation technology system in all aspects and finally determined the ideal embryo compensation technology process, which is to inject 3-5 human donor cells from the mulberry to early blastocyst stage to construct a chimeric embryo. After culturing the chimeric embryo in an embryo culture medium and stem cell culture medium mixed in equal proportions for 24 hours, the chimeric embryo is transplanted into a surrogate pig with a synchronized estrus cycle to obtain a chimeric pig fetus.

Research diagram. Photo provided by the interviewed units

The research team finally succeeded in achieving xenogeneic regeneration of humanized mesonephros in vivo. The study strictly complied with relevant ethical regulations and international practices, and terminated the pregnancy within 3-4 weeks of gestational age.

"Finally, we obtained two mesonephric chimeric fetuses at gestational age of 25 days and three at gestational age of 28 days. The proportion of human cells in the mesonephros of these chimeric fetuses can reach up to 70%, and the proportion of mesonephric tubules formed by human cells can reach up to 58%." Dai Zhen, another co-corresponding author of the paper and a researcher at the Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, introduced that the results of immunofluorescence staining of key functional genes SIX1, SALL1, PAX2 and WT1 for kidney development proved that human donor cells have differentiated into functional cells expressing these genes, indicating that along with embryonic development, human donor cells in kidney-deficient pig fetuses will be able to support the generation of humanized kidneys.

This achievement demonstrates for the first time the feasibility of recreating humanized functional solid organs in large xenogeneic animals based on stem cell and embryo compensation technology. It is a critical first step towards using large animal models of organ defects to perform xenogeneic organ regeneration in vivo, and is of great significance in solving the problem of severe shortage of donor organs.

Source: Science and Technology Daily