In embryonic development, the liver is not only a metabolic organ, but also crucial for the development of the blood and the immune system. How these different cell types work together in the embryo is still unclear. Yet it is precisely here that the switch for the development of early childhood liver diseases and leukemias could be flipped. However, it is extremely difficult to observe the disease processes in the developing liver. This can be facilitated by “blood-liver organoids”, which Dr. Milad Rezvani is developing in his research group at the Charité.
Biliary atresia is a serious disease involving the development of the liver and the immune system. In this case, the "drainage tubes" of the liver - the bile ducts – are lost due to an excessive inflammatory reaction. As a result, the bile produced by the liver and stored in the gallbladder can no longer flow into the small intestine. It backs up in the liver, presses on the liver tissue and gradually destroys it. Without surgery, the disease is fatal. Biliary atresia is the most common reason for liver transplantation in newborns. About one in 30.000 children is born with this defect in Germany.
"Despite this severe disease burden, little research is done on biliary atresia compared to leukemias, for example," says Dr. Milad Rezvani of the Department of Pediatrics with a focus on gastroenterology, nephrology and metabolic medicine at Charité. He wants to change that. With his Emmy Noether Junior Research Group, funded by the German Research Foundation (DFG), he is researching the causes and therapeutic strategies of chronic liver diseases. Biliary Atresia often develops in the fetal liver before birth. At this early stage of human life, the liver is primarily a blood-forming organ. Meanwhile, metabolic processes are taken over by the mother's liver.
Three-dimensional tissue models in the petri dish
Dr. Milad Rezvani and his team have succeeded in developing blood-liver organoids that can be used to observe disease processes at the cellular and molecular levels. Organoids, often referred to as miniature organs, are cell culture models that represent a tissue three-dimensionally in the Petri dish. Researchers usually grow them from stem cells that are not yet or barely differentiated. They can develop into any cell type, such as heart or kidney cells, muscle cells or neurons. In Milad Rezvani's laboratory, they become liver organoids that are permeated by various blood and immune cells, as in the fetal liver. "Liver cells don't develop in a vacuum," Dr. Rezvani explains, "but together with white blood cells and other cells of the body's defense system." And like real liver cells, the liver cells created by his group produce red blood cells - visible as red spots between the rice-grain-sized clusters of cells.
"Our organoids are a kind of window into a previously inaccessible organ, the fetal liver," Dr. Rezvani says. The scientist and pediatrician hopes to use them to elucidate the previously unknown cause of biliary atresia. In order to detect and distinguish between possible environmental and genetic factors, he plans to develop liver models from patients' own stem cells in the near future. He is also maturing blood liver organoids in order to use them as a disease model for diseases in adults, for example fatty liver hepatitis, now the most common chronic liver disease. In this case, the liver becomes fatty and inflamed. It is not uncommon for it to require a liver transplant. Rezvani's team is looking for the cells that cause the inflammation - in order to switch them off and thus reduce the inflammation. In addition, he plans to use blood-liver organoids to study the progression of neonatal leukemias. "We can create the leukemia-causing mutation in the blood," the scientist explains, "to observe how leukemia develops as cells interact in the tissue."
Awake liver cells with genetic scissors
This genetic manipulation works much better in organoids than in cells derived from animal models. For example, liver cells that slip into an identity crisis in the course of chronic liver disease and no longer behave like liver cells can be genetically reactivated in the Petri dish. "With the help of the CRISPR gene scissors, we can intervene in a liver cell in such a way that it once again does what a liver cell needs to do," explains Dr. Rezvani. In this way, miniature organs help reduce the number of animal searches. "New gene therapies can be tested on organoids first. Animal experiments are then only necessary to confirm the experiments in the living organism," the researcher explains. Another advantage, he says, is that organoids are available almost indefinitely, "because their cell source never dries up."
Currently, the group is working with a startup on an analysis system that can use artificial intelligence (AI) to detect damaged cells in an organoid. Until now, it has been necessary to stain the cells before microscopy. "It would be a dream come true and would advance liver research tremendously if we could save ourselves the extremely complicated and time-consuming process of killing and staining cells," enthuses Dr. Milad Rezvani. Toxicology studies, which are used to investigate the effects of drugs in a high-throughput process, would also produce results even faster.
The liver from the lab
Also in the future is using organoid technology to grow organ replacements. "It's not completely unrealistic," says Dr. Milad Rezvani, "we can already develop a tissue-like construct." This tissue construct could be "seeded" onto a scaffold, along which the organ would then grow. It will be a long time before the first liver comes out of the lab. But the Charité researcher has already held the first talks about possible projects.
(Text: Jana Ehrhardt-Joswig)
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