Intestinal cells change functions during their lives

Date:
March 1, 2022
Source:
Hubrecht Institute
Summary:
Intestinal cells can change specializations during their lives. The
BMP signaling pathway -- an important communication mechanism
between cells - - appears to be the driver of these changes,
according to research with organoids and mice. The study offers
new insights into potential targets for the treatment of metabolic
diseases.



FULL STORY ========================================================================== Intestinal cells can change specializations during their lives. The BMP signaling pathway -- an important communication mechanism between cells
- - appears to be the driver of these changes. That is wat scientists
from the groups of Hans Clevers (Hubrecht Instituut) and Ye-Guang Chen (Tshinghua University, Beijing) have concluded after research with
organoids and mice. The study will be published inCell Reports on 1 March
2022 and offers new insights into potential targets for the treatment
of metabolic diseases.


==========================================================================
The intestinal wall is made up of different types of cells. Some are for instance responsible for the uptake of nutrients, while others produce hormones. It was long thought that after their formation, intestinal cells specialize in one function that they continuously perform until they die.

However, recent studies show that these cells can change specializations.

Researchers from the groups of Hans Clevers and Ye-Guang Chen (Tsinghua University, Beijing) now discovered that these changes are driven by
the BMP signaling pathway.

Driver of change The BMP signaling pathway is one of many signaling
pathways in the body. Such pathways form lines of communications between
cells: with the production of a protein by one cell, it gives a signal
to the next cell, which in turn produces proteins. Eventually, this
whole cascade of protein production triggers certain processes -- for
example processes that are important during embryonic development. Joep
Beumer, one of the researchers on the project, explains: "We knew that
BMP signaling plays an important role in the initial specialization of intestinal cells. What we now discovered, is that it is also the driver
of changes in the specializations of these cells over their lifetimes.

Migration Intestinal cells arise from stem cells that lie in indentations
(i.e. the crypts) of the intestinal wall. These intestinal cells then
migrate up the intestinal villi. During their migration, they perform
a certain function, for example the absorption of nutrients or the
production of hormones. Once they reach the top of the villi, they
die. "The function of intestinal cells changes during their migration
along the villi. 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," says Beumer. 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.



========================================================================== Human organoids The scientists at the Clevers lab used intestinal
organoids for their research.

These are tiny 3D structures that can be grown in the lab and that mimic
the function of the gut. In these miniature guts, the researchers were
able to mimic conditions of low or high BMP signaling, similar to the
altering environment along the intestinal villi. Using 'Single cell RNA sequencing', a technique that makes it possible to see which genes are
active and which ones are not, they made a surprising discovery. Jens
Puschhof explains: "When BMP was active in the organoids, the cells in
these miniature guts were identical to the cells located in the top of
the villi, while inactivation of BMP made the cells in the organoids
resemble the cells located in the lower parts of the villi. In other
words, zonation turned out to be dependent on the BMP signaling pathway."
Mouse model The results found in organoids had to be confirmed in living organisms.

Colleagues from the group of Ye-Guang Chen used a mouse model in which
BMP signaling could be turned off in the gut. In mice with an inactive
BMP signaling pathway in the gut, 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.

Methodological implications The study, to be published in Cell
Reports, has important implications for the use of organoids for
research. "Normally, researchers inhibit BMP signaling in organoids,"
says Fjodor Yousef Yengej. "Although this proved beneficial for growth,
not all functions of the gut are represented in these cultures."
Activation of BMP signaling may be required for research into certain
topics, such as fat absorption.

Treatment of metabolic diseases In addition to providing these new
fundamental insights into the functions of intestinal cells during
their lives, the study 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. 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," Beumer concludes. BMP inhibitors targeting the gut are yet to be developed, but would have
broad beneficial effects on metabolism.

========================================================================== Story Source: Materials provided by Hubrecht_Institute. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Joep Beumer, Jens Puschhof, Fjodor Yousef Yengej, Lianzheng Zhao,
Adriana
Martinez-Silgado, Marloes Blotenburg, Harry Begthel, Charelle Boot,
Alexander van Oudenaarden, Ye-Guang Chen, Hans Clevers. BMP gradient
along the intestinal villus axis controls zonated enterocyte
and goblet cell states. Cell Reports, 2022; 38 (9): 110438 DOI:
10.1016/ j.celrep.2022.110438 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220301131042.htm

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