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Immune cells influence balance of intestinal stem cell renewal and maturation

Scientists have discovered that intestinal stem cells interact with nearby immune cells in a bi-directional manner that affects both the renewal of this stem cell source and remodeling of the intestinal lining during infection. The intestinal lining is constantly regenerating, in humans about once a week, with its regenerative capacity depending upon resident stem cells. Within the intestine, stem cells must be able to mature into specific cell types to replace old or damaged cells, and they also must divide and maintain their numbers as a source of future cell lineages. The replenishment of mature intestinal cells is especially important during gut infections, when the intestinal lining may be severely damaged by the pathogen and the resulting inflammatory response. The scientific community has focused on discovering how the stem cells’ environment of neighboring cell types and signals supports them in their important work maintaining the gut.

A team of investigators focused on investigating the role of immune cells residing in the intestine, including the chemical signals they release, called cytokines. They showed that intestinal stem cells from male and female mice produce a class of molecules, called “MHC II” molecules, typically only found on cells that signal to immune cells when detecting an infectious or “foreign” protein. Next, they mixed mouse intestinal stem cells in a dish with immune cells (from female mice) and a test protein that the immune cells could recognize. The stem cells used their MHC II molecules to present this protein to the immune cells, which became activated and secreted cytokines. To explore these interactions in a model more closely resembling the intestine, they turned to mouse intestinal organoids—miniature tubes of cells in culture that recapitulate some of the features of the intestine. Adding different types of the immune cells, or the cytokines they produce, modified the balance between the number of stem cells present and how many of them matured into specific intestinal cell types within the organoids. To study the stem cells during infection, the researchers moved to a whole-organism model. They gave female and male mice either Salmonella bacteria or a parasitic worm, and found that interactions between intestinal stem cells and immune cells were important for stem cell maturation into distinct cell types that reconstitute the intestinal lining during infection.

These studies performed in a wide range of experimental models—from single cells to organoids to whole animals—demonstrate the importance of crosstalk between intestinal stem cells and neighboring immune cells for maintaining the stem cell pool and healthy intestinal lining in both healthy and infected states. More research is needed to understand how these interactions affect the balance between renewal of the stem cell pool and maturation into cell types that may be needed at a given time to perform distinct functions within the intestine.

Biton M, Haber AL, Rogel N,…Xavier RJ. T helper cell cytokines modulate intestinal stem cell renewal and differentiation. Cell. 175: 1307-1320, e22, 2018.

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