The inner lining of the gut regenerates entirely every four to seven days, thanks to stem cells in the intestinal epithelium. Yet much remains shrouded in mystery regarding stem cells and what causes them to decide to divide or differentiate into specialized cells.

An article published in the journal Nature on July 13, 2022, “Retrograde movements determine effective stem cell numbers in intestinal crypts” reveals a new mechanism that shows that the number of functional stem cells in the intestinal epithelium is determined by a dynamic regulation of the location of stem cells in the small and large intestines. The active process of retrograde movement of stem cells described in the study uncovers a new route of experimentally and pharmacologically regulating stem cells in different parts of the intestines.

From left to right, Edouard Hannezo, professor at ISTA, (left, © ISTA/Nadine Poncioni) and Bernat Corominas-Murtra, previously postdoc at ISTA and now assistant professor at the University of Graz (right, © University of Graz/Konstantinos Tzivanopoulos).[left, © ISTA/Nadine Poncioni) (right, © University of Graz/Konstantinos Tzivanopoulos)]
PhD student Maria Azkanaz, and former postdoctoral fellow Bernat Corominas-Murtra, PhD, are the co-first authors of the collaborative study led by Benjamin Simons, PhD, professor at The Cavendish Laboratory at the University of Cambridge, Pekka Katajisto, PhD, professor at the Karolinska Institute in Stockholm, Edouard Hannezo, PhD, professor at the Institute of Science and Technology Austria (ISTA), and Jacco van Rheenen, PhD, professor at The Netherlands Cancer Institute in Amsterdam.

Using intravital microscopy, the team studied changes in the locations of labelled stems cells at the bottom of small and large intestinal crypts—deep and narrow pockets in the wall of intestines that exist between projections (villi) of the intestinal wall into the lumen.

“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 the tip of the surrounding villi,” Corominas-Murtra said. “There they differentiate into functional cell types that allow intestinal function and 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.”

The prevailing view attributes the stem-ness of stem cells to the intrinsic biochemical properties of the cell, estimable by the expression of biomarkers. Therefore, the investigators were initially perplexed when they found that many stem cells in the large and small intestines that expressed the proliferative signature LGR5 were not retained in the pool of stem cells in the intestinal crypts but were pushed out of the crypts, making no contribution to the long-term renewal of the lining of the gut.

“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,” said Corominas-Murtra.

Intestinal villi
Stem cells divide at the bottom of the intestinal crypts and the resulting cells are pushed upwards to the top pf the villi where they are discarded (Shuttershock).

These observations intrigued the researchers and led them to investigate why some cells are retained as stem cells and others are discarded. They found a new location-dependent mechanism that regulates the number of stem cells in the intestinal crypts.

“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 said.

In addition to passive cellular movement directed out of the intestinal crypts, the authors found these cells also move actively in random directions, back and forth, in and out of the crypts. Therefore, cells pushed up can move back into the base of the crypt and continue to replenish the epithelium.

The team found that this active retrograde movement of stem cells in intestinal crypts is regulated by a developmental signaling mechanism called Wnt-signaling. When the researchers suppressed this active retrograde movement using chemical inhibition, they found the number of functional stem cells reduced.

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

The current work builds on earlier mathematical modeling studies by the team that had described stemness and the probability of survival of a lineage of cells emerging as a phenomenon from the stochastic competition for space. Using the model, the investigators could predict the number of functional stem cells in the small and large intestines. Studies by other research groups have designed experiments based on microscopy and genetics to test these predictions and found them to be accurate.

These findings raise new questions about the origin and functional fate of stem cells along the intestinal tract and their impact on intestinal pathology. For example, Stephanie Ellis, PhD, postdoctoral fellow at the Rockefeller University and assistant professor at the Max Perutz Labs Vienna, and Elaine Fuchs, PhD, professor at the Howard Hughes Medical Institute at Rockefeller University, who review the study in a News & View article in the same issue of the journal ask, “In humans, cancers of the small intestine are much rarer than those of the large intestine. Could this be explained, at least in part, by the absence of retrograde migration in the large intestine’s crypts?”

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