Lymphatic capillaries are key to mediating stem cell differentiation in the intestines, and researchers find they produce key proteins to control this mechanism.
Intestinal tissue needs to be continuously regenerated and replaced to fulfill the intestine’s role as a barrier to pathogens whilst absorbing essential nutrients. The underlying communication pathway of this mechanism is not fully understood, but a recent study published in Cell Stem Cell by researchers at The Rockefeller University (NY, USA), finds that lymphatic capillaries act as the signaling hub in this mechanism.
Epithelial stem cells in the intestine are responsible for the constant tissue repair needed. Depending on the local microenvironment, known as niches, stem cells either differentiate into specialized cells to replace the intestinal lining or renew and replenish the reserve of stem cells. If there is poor coordination of this mechanism, intestinal disorders such as inflammatory bowel disease or certain cancers can occur.
“The key to treating these diseases will be to figure out who talks to whom in this ecosystem and how we can reset the communication networks,” explained Rachel Niec, the first author of the study.
Researchers developed a strategy to return cardiomyocytes to a stem cell-like state to promote the regeneration of heart muscle cells.
This study found that stem cells integrate cues from their surroundings to coordinate their behavior across the tissue through networks of nearby vasculature, and their activity is regulated by lymphatic capillaries – fine vessels that transport immune cells and drain fluids from tissues. Using this molecular guidance, the stem cells either repopulate the intestinal lining by producing daughter cells or self-renew. When the stem cells renew, they remain in what is called a ‘crypt’, which is found at the base of densely packed indentations in the intestinal lining.
“To understand how stem cells balance self-renewal with differentiation, we needed a more complete picture of crypt niches,” explained Marina Schernthanner, a co-author.
To study these crypts in more detail and identify cell types and signaling molecules at specific locations, the researchers used a variety of techniques including single-cell and spatial transcriptomics. They found that lymphatic capillaries have connections with stem cells in the crypt and produce proteins that are known to be important for stem cell functioning. One of the proteins identified called REELIN had previously been overlooked, the researchers explained.
The researchers found that REELIN contributed significantly to mediating communication between lymphatic capillaries and stem cells. To test this further, the researchers used intestinal organoid cultures with altered amounts of REELIN, as well as mice that were genetically suppressed against producing the protein. The results showed that REELIN directly controls the regenerative behavior of these stem cells.
These results highlight a relatively new concept of how the lymphatic system is involved with stem cell function and could lead to an improved understanding of intestinal disorders and new treatment options.
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