How the gut replaces and repairs itself

image: Lateral view of the small intestine with lymphatic capillaries in yellow and intestinal stem cells in pink.
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Credit: Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development at Rockefeller University

To act as a robust barrier against pathogens while absorbing necessary nutrients, the intestinal lining must regenerate daily to stay up to the task. The gut’s resident stem cells are responsible for meeting this need for constant repair and replenishment, but each stem cell faces decisions that depend on the general conditions of the gut and the needs at the time. Bad decisions and poor coordination could lead to bowel disease or cancer.

A new study suggests that stem cells are able to integrate signals from their environment and coordinate their behavior across tissue through networks of vasculature in their immediate vicinity.

Rockefeller scientists discovered that lymphatic capillaries – fine vessels that transport immune cells and drain fluids from tissues – represent a signaling center that communicates with stem cells to regulate their activity. Thanks to the molecular guidance of lymphatics, stem cells produce daughter cells to repopulate the intestinal mucosa or self-renew to replenish the stem cell reserve.

The resultspublished in the journal Cell Stem Cell, provide new insights into primary gut components whose disrupted communication may contribute to gut disorders, such as inflammatory bowel disease. “The key to treating these diseases will be figuring out who is talking to whom in this ecosystem and how we can reset the communication networks,” says Rachel Niec, clinician scientist in the lab of Elaine Fuchs.

Communications in the crypt

Intestinal stem cells reside in so-called crypts, located at the base of densely packed indentations in the intestinal lining. Stem cells can renew themselves and remain in the crypt, or differentiate into specialized cells, which then migrate out of the crypt to replenish the intestinal mucosa. “To understand how stem cells balance self-renewal with differentiation, we needed a more complete picture of crypt niches,” says Fuchs lab graduate student Marina Schernthanner.

To zoom into the crypt, the team used a suite of techniques, including single-cell and spatial transcriptomics, which allowed them to identify cell types in specific locations and study their signaling molecules. The results showed that lymphatic capillaries, which form an intimate connection with stem cells in the crypt, produce a number of proteins known to be important for stem cell function.

A previously underestimated protein, REELIN, has emerged as a prime candidate for mediating communications between lymph cells and stem cells. By manipulating the amount of REELIN in lab-grown intestinal organoid cultures in some experiments and genetically suppressing it in mice in others, the researchers found that REELIN directly mediates the regenerative behavior of intestinal stem cells.

The involvement of the lymphatic system in the functioning of stem cells is a relatively new concept. A previous study by the Fuchs team revealed that the lymphatics are also closely involved with skin stem cells and play a key role in hair regeneration. There, however, it is the hair follicle stem cells that signal to the lymph capillaries. By controlling their interactions with the lymphatics, stem cells synchronize hair regeneration through the tissue. “This suggests that lymphatics may be a conserved feature of stem cell niches, but their relationship to stem cells is likely tailored to the needs of each tissue,” Niec says.


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