New research shows how stem cells act in the intestine

The use of stem cells in medical therapy is a hot issue. Scientists are still unsure of how cells decide to divide or differentiate in order to regenerate organs. Recently, scientists discovered a new biophysical mechanism that controls stem cells in mice’s intestines.

New research shows how stem cells act in the intestine
Cross section of intestinal epithelium. Stem cells divide at the bottom of the intestinal crypts and the resulting cells are pushed upwards to the top of the villi where they are discarded. Image Credit: Shutterstock.

There, a stem cell is distinguished not just by its own internal molecular markers but also by its position and mobility within its environment. Possible new therapies may be affected by this.

The Human stomach is a miraculous location. The inside of both small and large intestines are coated with a particular layer of cells that absorb nutrients and water from the food that ate while keeping pathogens away.

The intestinal epithelium is the name of this layer. It uses stem cells to totally recreate itself every four to seven days. These are a unique form of cell that can regenerate by dividing as well as differentiating to produce any other type of cell to replenish the organs. However, it is still unclear to scientists how precisely stem cells make these choices or what constitutes a stem cell.

Together with a global team of experimental researchers led by the Jacco Van Rheenen team in Amsterdam, Edouard Hannezo, professor at ISTA, Bernat Corominas-Murtra, formerly a postdoc at the Institute of Science and Technology Austria (ISTA), and Bernat Corominas-Murtra, assistant professor at the University of Graz, investigated the stem cells in the intestinal epithelium.

Researchers discovered a fascinating new mechanism that could alter how stem cells are seen. The journal Nature has recently published its results.

The intestinal epithelium consists of a single, continuously regenerating layer of cells. It is all throughout the villi, which resemble tiny tentacles and coat the small and large intestines’ interiors. Intestinal crypts are tiny tissue pockets that exist between the villi. That name could evoke some mystery, and that might be a fair representation of what really transpires there.

At the bottom of the crypts, stem cells in the epithelium are constantly dividing. Some of the resulting cells remain as stem cells in the crypt and the others are pushed outwards towards to tip of the surrounding villi, there, in the end, they differentiate into functional cell types that allow intestinal function and which are discarded after a few days. This happens all the time inside your body and if this mechanism breaks down, you can get into serious medical trouble.”

Bernat Corominas-Murtra, Assistant Professor, Institute of Biology, University of Graz

The scientists were originally puzzled when investigating these stem cells in the small and large intestines.

How we usually think of stem cells is that being a stem cell is determined by intrinsic biochemical properties of a cell—something like a biochemical marker we can identify. We found that among the cells that had this traditional stem cell marker, many of them never actually worked as stem cells but were pushed out of the crypts to be discarded instead, without contributing at all to the long-term renewal of the gut.”

Bernat Corominas-Murtra, Assistant Professor, Institute of Biology, University of Graz

Corominas-Murtra added, “We also saw that while classical markers predicted about the same number of stem cells in both the small and large intestines, there were about twice as many of them actually working as stem cells in the small intestine than in the large intestine.”

Thus, the researchers sought to understand what decides whether cells truly function as stem cells and discovered a novel, unexpected mechanism that controls the stem cells in the crypts.

We found that whether you behave as a stem cell or not is all about your location! Cells in the epithelium are not just pushed outwards from the crypt by the cell divisions below them—like on a conveyor belt—but there is another kind of motion involved,” Corominas-Murtra explained.

The researchers discovered that epithelial layer cells actively travel back and forth along a conveyor belt-like path in random orientations. By doing this, cells in undesirable locations that would typically be forced out by the conveyor belt may change their position, land back at the bottom of the crypt, and then operate there once more as stem cells to divide as well as replenish the epithelium.

These movements constitute a new environmental mechanism that determines which cells get to functionally act as stem cells. In the small intestine, the molecular signal regulating the movements is stronger than in the large intestine, so cells can move more frequently back into the crypt.”

Edouard Hannezo, Professor, Institute for Science and Technology Austria

Edouard Hannezo discusses how their discoveries could have implications, “This explains why there are more actually working stem cells in the small intestine than in the large ones. This could have major implications for our understanding of what a stem cell actually is and how to use them in medical applications.”

This understanding expands on earlier work by the Van Rheenen group, Edouard Hannezo, and Bernat Corominas-Murtra at ISTA. Corominas-Murtra and Hannezo, who were trained in physics, developed a sophisticated mathematical model of the intestinal epithelial layer that took into account the movement of the cells both away from and back toward the crypt.

Researchers were able to forecast the number of functional stem cells in the small and large intestines using their approach. Other research teams from all throughout Europe created studies utilizing the most up-to-date microscopy and genetics techniques to evaluate the predictions, and researchers discovered they were right.

Even after trying to block the chemical signal in the crypts, they saw that the number of functional stem cells altered as expected.

Source:
Journal reference:

Azkanaz, M., et al. (2022) Retrograde movements determine effective stem cell numbers in the intestine. Nature. doi.org/10.1038/s41586-022-04962-0.

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