Scientists develop new organoid model to study thymus function

Researchers from the Organoid group have developed a new organoid model that can be used to study the thymus. The organoids, derived from mouse thymus tissue, specifically model thymic epithelial cells (TECs). These cells are responsible for training the T cells of the immune system to properly respond to pathogens. It is the first laboratory model that enables long-term culture of TECs, which presents new opportunities to study their function. Ultimately, this could also bring new insights into the treatment of patients with impaired thymus function. The study was published in Cell Reports on 27 March 2024.

Our immune system protects us from pathogens like viruses and bacteria. In order to effectively detect and eliminate these, several types of white blood cells are required, including T cells. Before they can do their job, T cells need to be trained to only attack pathogens and not the body’s own cells. This happens in the thymus, a small organ located behind the breastbone. The ‘teachers’ in this training process are called TECs. They present all kinds of molecules to the T cells and eliminate those that do not respond properly. The end result is mature T cells that enter the bloodstream, ready to respond to pathogens.

Organoids to model the thymus
Researchers studying TECs need a way to grow these cells in the laboratory. The Organoid group has now succeeded in developing a new system: TEC organoids, based on thymus tissue from mice. First author on the study Sangho Lim explains the advantage of these organoids compared to previous systems: “Before, it was not possible to keep TECs alive in culture for long. This made it difficult to study them and to do experiments. Our TEC organoids can be kept in culture for over two years, so that allows for long-term experiments.”

Compared to other culture systems, the organoids are also a better representation of the diversity of TECs in the body. Specifically, two different subtypes of TECs exist, cortical and medullar TECs, depending on where in the thymus they are present. These subtypes also have specific functions in training T cells. “By adding a different cocktail of molecules to the organoids, we can direct the cells to specialize into the cortical and medullar subtypes. Before, it was difficult to get this diversity of TECs in culture,” Lim says.

Training T cells
Lim and his colleagues also confirmed that the TECs in the organoids were capable of doing their job: training T cells. “We first mixed the organoids together with immature T cells in culture. We then followed their maturation by looking at the molecules CD4 and CD8 on the outside of the cells. In the body, immature T cells acquire and lose these molecules in a specific order during their development. This corresponded nicely with what happened in our culture plates,” says Lim.

The researchers obtained similar results in mice born without a thymus. Lim: “These mice have very low numbers of mature T cells in the blood, because they have no thymus to train them. When we transplanted our TEC organoids under their skin, we saw a very clear increase of the amount of mature T cells in their blood.” It therefore seems that the TEC organoids were capable of taking over the function of the missing thymus by stimulating T cells to mature.

New possibilities
The mouse TEC organoids open up new possibilities for scientists studying the thymus and T cell maturation. From a clinical perspective, this is especially relevant for patients with impaired thymus function, a condition that can be due to specific cancer treatments or neonatal heart surgeries. “In the future, we might be able to explore transplantation of TEC organoids as a treatment strategy to restore thymus function. But a lot of work still needs to be done before we get there,” Lim concludes. 

Publication
Derivation of functional thymic epithelial organoid lines from adult murine thymus. Sangho Lim, Gijs J. F. van Son, Ni Luh Wisma Eka Yanti, Amanda Andersson-Rolf, Sam Willemsen, Jeroen Korving, Hong-Gyun Lee, Harry Begthel, and Hans Clevers. Cell Reports, 2024.

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About Hans Clevers

Hans Clevers is advisor/guest researcher at the Hubrecht Institute for Developmental Biology and Stem Cell Research (KNAW) and at the Princess Máxima Center for Pediatric Oncology. He holds a professorship in Molecular Genetics from the Utrecht University and is an Oncode Investigator. Hans Clevers has been the Head of Pharma Research and Early Development (pRED) at Roche since 2022. He previously held directorship/President positions at the Hubrecht Institute, the Royal Netherlands Academy of Arts and Sciences and the Princess Máxima Center for pediatric oncology.

About the Hubrecht Institute

The Hubrecht Institute is a research institute focused on developmental and stem cell biology. Because of the dynamic character of the research, the institute has a variable number of research groups, around 20, that do fundamental, multidisciplinary research on healthy and diseased cells, tissues and organisms. The Hubrecht Institute is a research institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), situated on Utrecht Science Park. Since 2008, the institute is affiliated with the UMC Utrecht, advancing the translation of research to the clinic. The Hubrecht Institute has a partnership with the European Molecular Biology Laboratory (EMBL). For more information, visit www.hubrecht.eu.