Scientists have discovered a previously unknown level of organisation inside the intestine: support cells once believed to form a single group are actually four distinct cell populations with different roles.
The discovery, by researchers at the Hebrew University of Jerusalem in Israel, provides new insight into how the intestine repairs itself and could eventually contribute to new approaches for treating intestinal disorders.
The intestine replaces its inner lining every few days, making it one of the body’s fastest-renewing tissues. This constant renewal depends on stem cells located in tiny pockets called crypts. Newly formed cells migrate upward towards finger-like structures called villi, where they mature before eventually being shed from the body.
Scientists already knew that a network of specialised support cells, called Foxl1-lineage mesenchymal cells, sits beneath the intestinal lining and helps maintain these stem cells. Until now, these support cells were generally believed to function as a single group.
The study, led by doctoral student Amal Gharbi and Dr Michal Shoshkes-Carmel, found that these cells are actually made up of four distinct populations. Each population occupies a different area of the intestine, has its own genetic program, and produces different molecular signals.
“Our findings show that these cells are far more specialized than we previously appreciated,” said Shoshkes-Carmel. “Each subtype appears to provide a different set of signals depending on its location, helping coordinate stem cell activity, tissue renewal, immune responses and the overall organization of the intestine.”
The study was published in the peer-reviewed journal Cellular and Molecular Gastroenterology and Hepatology.
Decoding Intestinal Repair
Using single-cell RNA sequencing, a technique that analyses the activity of individual cells, along with advanced imaging techniques, the researchers created the first detailed map of Foxl1-lineage cells along the intestine’s crypt-to-villus structure — from the stem-cell-containing pockets at the base of the tissue to the villi at its surface.
The analysis revealed that each of the four cell populations has a unique genetic signature and produces its own combination of signalling molecules. These signals influence intestinal stem cells, neighbouring intestinal cells, blood vessels and immune cells, revealing previously unknown communication pathways inside the tissue.
Rather than relying on one type of support cell performing many functions, the intestine appears to use a coordinated network of specialised cells. Each population creates a local environment that guides nearby cells and helps maintain healthy tissue.
“Instead of finding one type of support cell doing many jobs, we discovered a whole community of specialised cells,” said Gharbi, the study’s first author. “Each group occupies its own neighbourhood in the intestine and appears to communicate with nearby cells in a different way. It’s like uncovering an entirely new layer of organization.”
The researchers found that support cells surrounding the crypts were especially rich in signals that help maintain intestinal stem cells. Other support cells located higher along the villi were more closely linked to immune regulation, tissue structure, nutrient sensing and metabolic responses.
Together, these four populations create a support network that organizes the intestine from its base to its surface while coordinating the processes needed to maintain healthy tissue.
While the findings do not represent an immediate treatment, they provide a more detailed understanding of the biological processes involved in intestinal repair. Over time, this knowledge could help researchers explore more targeted approaches for conditions such as inflammatory bowel disease, intestinal injuries and other disorders in which the intestine’s ability to heal is impaired.
The researchers’ next step is to determine the precise role of each newly identified cell population by selectively changing their activity in experimental models. Future studies will examine how these cells contribute to regeneration, stem cell support, immune signalling and tissue repair, potentially identifying new targets for future therapies.