Embryonic Humanized Kidneys Inside Pigs

Guangzhou Institutes of Biomedicine and Health researchers have successfully created chimeric embryos containing a combination of human and pig cells. When transferred into surrogate pig mothers, the developing humanized kidneys had normal structure and tubule formation after 28 days. 

The work appears in the journal Cell Stem Cell.

The researchers focused on kidneys because they are one of the first organs to develop, and they’re also the most commonly transplanted organ in human medicine.

The team’s technique depends on three key components:

• First, they created a niche within the pig embryo so that the human cells would not have to compete with pig cells by using CRISPR to genetically engineer a single-cell pig embryo so that it was missing two genes that are needed for kidney development.

• Second, the researchers engineered human pluripotent stem cells — cells that have the potential to develop into any cell type — to make them more amenable to integration and less likely to self-destruct by temporarily shutting down apoptosis. Then, they converted these cells into “naïve” cells resembling early human embryonic cells by culturing them in a special medium.

• Third, before implanting the developing embryos in surrogate sows, the researchers grew the chimeras in conditions that were optimized to provide unique nutrients and signals to both the human and pig cells, since these cells usually have disparate needs.

The researchers collected five chimeric embryos for analysis (two at 25 days and three at 28 days post-implantation) and found that they had structurally normal kidneys for their stage of development and were composed of 50-60% human cells.

The team also investigated whether human cells were contributing to other tissues throughout the embryos, which could have ethical implications, especially if abundant human cells were found in neural or germline tissues and the pigs were brought to term. They showed that human cells were mostly localized to the kidneys, whereas the remainder of the embryo was composed of pig cells.

Now that they have optimized conditions for growing humanized kidneys in human-pig chimeras, the team wants to allow the kidneys to develop for a longer duration. They’re also working to generate other human organs in pigs, including the heart and pancreas.

The long-term goal is to optimize this technology for human organ transplantation, but the researchers acknowledge the work will be complex and could take many years. 

Growing a fully functional humanized organ in a pig would require some additional steps because organs are composed of multiple types of cells and tissues. In this study, the researchers created a niche for only one subset of cells, which meant that the kidneys had pig-derived vascular cells, and this could cause organ rejection if they were used in a transplant scenario.

In the meantime, this technology could be used to study the development of human organs and developmental diseases.

“Before we get to that late state of making organs that can be on the shelf for clinical practice, this method provides a window for studying human development,” says Esteban. “You can trace the human cells you’re injecting and manipulate them so that you can study diseases and how cell lineages are formed.”

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Sources:

Jiaowei Wang, Wenguang Xie, Nan Li, Wenjuan Li, Zhishuai Zhang, Nana Fan, Zhen Ouyang, Yu Zhao, Chengdan Lai, Hao Li, Mengqi Chen, Longquan Quan, Yunpan Li, Yu Jiang, Wenqi Jia, Lixin Fu, Md. Abdul Mazid, Yanling Zhu, Patrick H. Maxwell, Guangjin Pan, Miguel A. Esteban, Zhen Dai, Liangxue Lai. Generation of a humanized mesonephros in pigs from induced pluripotent stem cells via embryo complementation. Cell Stem Cell, 2023; 30 (9): 1235 DOI: 10.1016/j.stem.2023.08.003

Cell Press. (2023, September 7). Researchers grow embryonic humanized kidneys inside pigs for 28 days. ScienceDaily. Retrieved September 26, 2023 from www.sciencedaily.com/releases/2023/09/230907130350.htm

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