Embryonic human kidneys grown in pigs

Porcine embryos

Normal pig embryo (top) and the chimera embryo with the human kidney. The red fluorescence marks human cells. © Wang, Xie, Li,Li, and Zhang et al./Cell Stem Cell, CC-by-sa 4.0

Kidneys are the most frequently transplanted organs in human medicine. Now researchers have succeeded for the first time in growing embryonic human kidneys in pigs. To do this, they implanted human stem cells into genetically modified pig embryos, which developed into kidneys. After the chimeric embryos had grown in surrogate pig mothers for 28 days, the humanized kidneys had a structure typical of this stage of development. As hoped, there were hardly any human cells found in other parts of the embryo. The technique could help better understand human organ development and possibly one day grow transplantable human organs in pigs.

The kidneys remove waste products from the blood and ensure that they are excreted in the urine. They are also involved in regulating blood pressure and the body's water balance. If the kidneys no longer function, those affected have to have their blood cleaned using dialysis several times a week or need a kidney transplant. However, the waiting list for donor organs is long, meaning it often takes years until an organ is available. Researchers are therefore trying to find a remedy in other ways. Their goal is to grow human organs in other species.

Solution to the problem of organ deficiency?

A team led by Jiaowei Wang from the Chinese Academy of Sciences in Guangzhou has now taken an important step in this direction. They successfully created chimeric pig embryos with human kidneys and cultured them in surrogate pig mothers for 28 days. “The creation of human organs in other large mammals would be a groundbreaking solution to the problem of organ shortage,” the researchers write. “However, it faces many challenges.”

One of the key problems in previous studies was that human cells inserted into embryos of foreign species were displaced by the recipient tissue and did not develop further. In addition, human cells require different environmental conditions than, for example, pig cells, and the development speed of human and pig organs differs, which makes synchronization in the embryo complicated.

Chimeras in surrogate pig mothers

“To overcome the extremely low efficiency of interspecies chimeras, we started with several different mechanisms,” explains Wang’s colleague Guangjin Pan. “We have identified a number of critical factors that promote the formation of interspecies chimeras by facilitating cell competition.” First, the team modified the human stem cells so that two survival-promoting genes were particularly strongly expressed. In addition, they created a niche in the pig embryos by switching off the pig genes that are essential for animal kidney development. “We found that if you create a niche in the pig embryo, human cells naturally go into these spaces,” reports Wang’s colleague Zhen Dai.

Before implanting them into surrogate pig mothers, the researchers also grew the chimeric embryos under conditions that optimally supplied both the human and pig cells with nutrients and environmental signals so that both parts could grow. The researchers created a total of 1,820 embryos in this way and used them as surrogate mothers in 13 sows. Implantation worked in six sows and they became pregnant with the chimeric embryos. For ethical reasons, the researchers terminated the sows' pregnancy after 25 to 28 days.

Human cells, especially in the kidneys

An important question was whether human cells were also found in the brain, nervous system or germline of the chimeric pig embryos. In this case, it would be extremely ethically problematic to allow the chimeras to continue to develop. But the team gives the all-clear: “We saw very few human nerve cells in the brain and spinal cord and no human cells in the genital area, which suggests that the human pluripotent stem cells have not differentiated into germ cells,” reports Zhen Dai. Switching off additional genes in the pluripotent human stem cells could further reduce the risk of them differentiating into something other than kidney tissue.

In the kidneys, however, human cells made up a large proportion of 50 to 60 percent, as hoped. At the time of collection, they were in the so-called mesonephros stage, the second stage of kidney development, as the researchers determined. The typical renal tubules and cell buds were already visible, from which the ureters would arise with further development. “Our results show that it is in principle possible to create a humanized organ in pigs, opening an exciting avenue for regenerative medicine and an artificial window to study human kidney development,” the team writes.

Long way to transplantable organs

In future studies, the researchers want to further optimize the conditions for growing human kidneys in pigs and allow the kidneys to grow over a longer period of time. They are also working on creating other human organs such as the heart and pancreas in pigs.

However, whether such organs can actually be transplanted into humans is still uncertain and will require many years of further research and development. “Because organs are not made up of just a single cell line, we would probably have to manipulate the pigs in a much more complex way to get an organ where everything comes from humans. That would bring additional challenges,” says Wang’s colleague Miguel Esteban. However, the new technology could already help science beforehand. “Before we get to the point where we can produce organs for clinical practice, this method offers the opportunity to study human development,” says Esteban. “You can track and manipulate the human cells you inject to study disease and cell line formation.”

Source: Jiaowei Wang (Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, China) et al., Cell Stem Cell, doi: 10.1016/j.stem.2023.08.003

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