BMP Signaling Pathway Behind Changes to Intestinal Cell States

New research out of the Netherlands and China has identified the signaling pathway that triggers intestinal cells to change their specialization—findings that could offer new insights into potential targets for treating metabolic diseases.

The intestinal wall is made up of different types of cells, with distinct responsibilities such as uptake of nutrients and hormone production. It was long thought that, once formed, intestinal cells specialized in one function would continuously perform that function until they die. However, recent studies show that these cells can change specializations. Using organoids and mice, teams led by Hans Clevers at Hubrecht Instituut and Ye-Guang Chen of Tshinghua University (TU) further determined that the BMP signaling pathway—an important communication mechanism between cells—is behind specialization changes.

“We knew that BMP signaling plays an important role in the initial specialization of intestinal cells,” says coauthor Joep Beumer. “What we now discovered, is that it is also the driver of changes in the specializations of these cells over their lifetimes.”

Intestinal cells arise from stem cells that lie in indentations, also known as crypts, in the intestinal wall. These intestinal cells then migrate up the intestinal villi, performing their specialized functional along the way. Once they reach the top of the villi, they die. “The function of intestinal cells changes during their migration along the villi,” says Beumer. “They for example produce antimicrobial components in the lower parts of the villi (at the start), while they are involved in absorbing fats later on in their journey.”

This gradual change in the function of the cells is called zonation. “At the same time, the BMP signaling pathway is not very active in the crypts and in the lower parts of the villi, while it becomes more and more active higher up in the villi.

Using intestinal organoids that mimic the function of the gut, the Clevers lab team were able to mimic conditions of low or high BMP signaling, similar to the differing environments along the intestinal villi. Using single-cell RNA sequencing—a technique that makes it possible to see which genes are active and which are not—they found that, when BMP was active, the cells were identical to those at the top of the villi. When BMP was inactive, the cells resembled those in the lower portions. “In other words, zonation turned out to be dependent on the BMP signaling pathway,” says coauthor Jens Puschhof.  

To confirm the organoid results in living organisms, the TU team used a mouse model in which BMP signaling could be turned off in the gut. In mice with an inactive BMP signaling pathway, intestinal cells no longer changed specializations during their migration from the crypts to the villi. “That confirmed our conclusion: BMP signaling is the driver behind zonation of intestinal cells,” says Beumer.

The study, published recently in Cell Reports, may ultimately contribute to the development of new treatments for metabolic diseases. “In certain metabolic diseases, there is an accumulation of fat in parts of the body such as the liver, or an imbalance in gut hormones,” Beumer says. “We now know that active BMP signaling stimulates fat absorption, so if we can inhibit signaling in these patients, we can also influence fat absorption.”