Tuft cells act as regenerative stem cells in the human intestine

Intestinal tuft cells divide to make new cells when immunological cues trigger them. Additionally, in contrast to progenitor- and stem cells, tuft cells can survive severe injury such as irradiation damage, and contribute to the epithelium's regeneration. That is what researchers from the Organoid group of the Hubrecht Institute found using miniature human intestines grown in the lab. The findings, published in Nature on 2 October 2024, may have important implications for the regeneration of intestinal tissue after damage.

The human intestinal tract is responsible for the uptake of nutrients and the production of hormones. Additionally, it protects the gut from pathogens. These important functions are executed by specialized cells in the epithelium, the tissue that lines the intestines. The epithelium consists of different types of specialized epithelial cells, including tuft cells.

Function of tuft cells

Tuft cells are present throughout the intestinal tract as well as in many other organs. Most insights into the function and ontology of these cells come from research with mice. Studies showed that one specific category of tuft cells protects the gut from pathogens. When tuft cells sense the presence of pathogens, they signal to immune cells and to the epithelium to initiate a strong defense response. However, due to a lack of human research models, the function of tuft cells in the human intestinal tract remained unknown.

Miniature intestines

More than enough reason for the researchers from the Organoid group to delve deeper into this matter using the unique organoid technology they developed. They grew miniature intestines in a dish, which mimic the function of actual human intestines. The structures, called organoids, contain all the different intestinal cell types. Lulu Huang, co-first author of the paper together with Jochem Bernink and Amir Giladi, explains: “We used these organoids to carefully monitor the development and function of tuft cells. Moreover, this model enabled us to study the effect of radiation on the function of the organoids.”

Tuft cells act as reserve stem cells

One of the most important discoveries the researchers made was that tuft cells can proliferate when immunological cues trigger them. “Upon receiving such immunological signals, tuft cells divide to make new tuft cells, which can in turn transdifferentiate and generate all other epithelial cell types. Through this process, tuft cells can restore the wounded gut,” says Bernink.

Survival after damage

What is especially impressive about tuft cells is that they survive damage caused by irradiation. Where stem- and progenitor cells lose their ability to proliferate after such damage, tuft cells can survive and generate all different intestinal epithelial cell types. Huang: “We also grew organoids without tuft cells, and these organoids were unable to recover from radiation damage.” Tuft cells, therefore, play an essential role in repairing intestinal tissue upon damage.

Regeneration of tissue

“Tuft cells basically form a pool of reserve stem cells in the human intestines. A pool that is brought to action when damage has occurred,” Bernink explains. The findings, published in Nature, may have implications for regenerative medicine, a field of research that focuses on the repair and restoration of tissue. “In addition to more research into the exact regenerative function of human tuft cells, it would be interesting to study the function of tuft cells in other organs, for example in the liver, urinary tract and lungs,” Huang concludes.

Publication

Tuft cells act as regenerative stem cells in the human intestine. Lulu Huang*, Jochem H. Bernink*+, Amir Giladi*, Daniel Krueger, Gijs J.F. van Son, Maarten H. Geurts, Georg Busslinger, Lin Lin, Harry Begthel, Maurice Zandvliet, Christianne J. Buskens, Willem A. Bemelman, Carmen López-Iglesias, Peter J. Peters, Hans Clevers+. Nature 2024

* Authors contributed equally
+ Corresponding authors

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.