A study conducted primarily in mice found that acute inflammation can leave long-lasting changes in the intercellular matrix, altering the fate of stem cells in the intestine. Findings from seven biopsies of ulcerative colitis patients support a link to humans, but the road to a new diagnosis or treatment is still a long one.
The layer of cells lining the intestine is completely renewed every three to five days—the fastest turnover rate in the human body. This rapid renewal is essential for tissue that is exposed to mechanical wear, bacteria, and substances passing through the digestive tract. But new research fromWeitzman Institution of Science This suggests that even after the cells are replaced and the acute inflammation subsides, the environment in which they grow may remain damaged.
In the study, Published in the journal ImmunityThe researchers found that acute intestinal inflammation left mice with changes that lasted for more than a year in the intercellular matrix—the network of proteins and sugars that surrounds cells and provides them with support and biological signals.
The changes in texture affected the intestinal stem cells, causing them to produce cells that promote inflammation instead of normal mucosa. The researchers also identified similar cells in inflamed areas in seven biopsies from patients. Ulcerative colitisHowever, this is still early research: most of the experiments were conducted in mice and cell cultures, and no therapeutic trial was conducted in humans.
Not just packaging material
The intercellular substance, also known as Extracellular matrix The extracellular matrix, or ECM, was previously thought of primarily as a mechanical infrastructure that holds cells in place. In recent years, it has become apparent that it plays a much more active role: it stores proteins and signaling molecules, influences cell behavior, and helps determine whether tissue will regenerate properly.
The study was conducted in the laboratories of Prof. Irit Sagi and Dr. Moshe Biton from the Department of Immunology and Biological Regeneration at the Weizmann Institute. In a previous study, Sagi's group showed that changes in the intercellular matrix may occur even before inflammatory bowel disease can be identified by colonoscopy or biopsy.
While working on the previous study, Dr. Idan Adir noticed that short-term inflammation andChronic inflammation create similar changes in the intercellular matrix of mice. This raised the possibility that the matrix retains a kind of memory of the injury, even after the initial inflammatory response has passed.
The inflammation is gone, the damage remains.
To test the hypothesis, the researchers induced acute intestinal inflammation in mice and followed them for more than a year. During the inflammation, theIntestinal mucosa Immune cells secreted enzymes that break down proteins in the intercellular matrix.
After about a month, the mice recovered from the acute inflammation, but the intercellular matrix did not return to its previous state. It lost its rigidity, became more porous, and the intestinal structure remained distorted even after 80 days. Certain changes were observed even after 400 days.
To examine the effect of the damaged tissue, the researchers grew organoids—tiny three-dimensional structures that mimic the intestine—fromStem cells healthy. When the cells were grown on Intercellular tissue Taken from an intestine damaged by inflammation, they did not form a normal three-dimensional lining. Instead, a structureless cell surface was formed.
RNA sequencing showed that the stem cells did not mature into normal intestinal cells, but into epithelial cells that secreted chemical signals that attract immune cells and may perpetuate the inflammatory response.
The finding suggests a possible cycle: inflammation damages the intercellular tissue; the damaged tissue alters the development of stem cells; and the resulting cells encourage further inflammation.
The connection to humans is still rudimentary.
The researchers compared the cells generated in the experiments to a single-cell RNA sequencing dataset and seven biopsies taken from ulcerative colitis patients. They found that epithelial cells with similar inflammatory characteristics are also found in inflamed areas of the human intestine.
The similarity strengthens the possibility that the mechanism found in mice also works in humans, but seven biopsies is a small sample. Further studies in larger populations and with long-term follow-up are needed before the findings can be used to predict flare-ups or guide treatment choices.
Collagen 18 Changes cell fate
Researchers have identified a protein that may play a central role in maintaining inflammatory memory: collagen 18. Previous research found that the protein's accumulation in the intercellular matrix may be an early sign of inflammatory bowel disease. The new study shows that it may be more than just a marker.
Collagen 18 can trap signaling molecules and disrupt the transmission of signals to stem cells. As a result, the cells may differentiate into epithelial cells that promote inflammation.
When the researchers silenced the expression of collagen 18 in mice, the intercellular matrix did not suffer the same long-term damage and the chronic disease was prevented. This result places the protein as a potential target for developing treatments, but does not mean that a suitable treatment for humans has already been found.
Beyond the immune system
The treatments available inInflammatory bowel disease Focused largely on suppressing or regulating the immune system, these treatments have greatly improved the condition of many patients, but do not prevent all flare-ups and are not beneficial for everyone.
The new study also suggests examining the tissue environment within which immune cells and stem cells operate. In the future, it is possible that combining treatment of the immune system with treatment of the intercellular matrix will allow for action at earlier stages of the process.
Researchers are also investigating whether it is possible to detect protein fragments in the blood that are formed as a result of the changes in texture. If such fragments prove to be a reliable reflection of the state of the intestine, they could serve as the basis for less invasive tests. This option is also still in the research phase.
The study involved researchers from the Weizmann Institute of Science, Sheba Medical Center, Leopard University of Technology, and the University of Oulu in Finland. The study was led by Dr. Idan Adir under the supervision of Prof. Irit Sagi and Dr. Moshe Biton.
More on the subject on the science website
- Four hidden populations of supporting cells help the gut regenerate
- Stem cells in the gut sacrifice themselves to stop bacterial infection
- The secret is in the texture: Changes in intercellular texture may predict inflammatory bowel disease
- Without fasting or anesthesia: A noninvasive method for diagnosing inflammatory bowel disease
- A slippery, inflamed slope: the link between chronic inflammatory bowel disease and cancer
Questions and Answers
What is the intercellular substance?
It is a network of proteins and sugars that surrounds cells, providing them with physical support and biological signals. Research shows that it may also influence stem cell development and the inflammatory response.
What did the researchers find after the acute inflammation had passed?
In mice, changes in the structure and stiffness of the intercellular matrix were found even hundreds of days after recovery. The changes caused stem cells to develop into cells that promote inflammation.
Has a new treatment been found forCrohn's And ulcerative colitis?
Not yet. Silencing collagen 18 prevented the chronic process in a mouse model, but further studies are needed before such a treatment can be tested in humans.
Has the mechanism been proven in humans?
Cells with similar characteristics were found in seven biopsies from ulcerative colitis patients. This is preliminary support, but the sample is small and not sufficient for clinical proof.
For the original publication: Opening the original publication
