A study by the Weizmann Institute and the Hebrew University reveals a new immune defense mechanism: stem cells infected with Salmonella accelerate their maturation, stop reproducing, and help save intestinal tissue.
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Synonyms: Intestinal stem cells, intestinal stem cells, intestinal epithelium, immune system, immune defense, bacterial infection, Salmonella, Crohn's disease, inflammatory diseases, cell differentiation
SLUG: intestinal-stem-cells-bacterial-infection-defense
We all start our lives as a collection of embryonic stem cells – extraordinary cells that can mature and become any type of cell in the body. Even in adulthood, small populations of stem cells remain in the body, which are able to mature into different types of adult cells and regenerate some tissues. Stem cells are reluctant to mature, and like Peter Pan, can remain young for many years. Now, a team of researchers from the Weizmann Institute of Science and the Hebrew University of Jerusalem reveals that the eternal youth of the cellular world are able to forgo a long life, mature and die if infected with a bacteria – thereby saving the tissue. The findings of the new study, whichPublished this week in the scientific journal Nature Immunology, reveal the active role of stem cells in immune defense and indicate their possible involvement in inflammatory diseases and cancer.
All the cells in our body carry the same genetic code, but each one expresses different genes. As stem cells mature, a process called “differentiation,” they turn on certain genes and turn off others, gradually implementing the genetic program of the adult cell they are becoming and acquiring its characteristics. However, maturation comes at a heavy personal cost – the life span of a stem cell can be shortened from years to just weeks or days.
"In effect, the infected stem cell 'sacrifices' its life and sentences itself to imminent death, to prevent prolonged infection and allow the remaining stem cells to restore the tissue."
In a new study, led by Dr. Sacha Lavon from the lab of Dr. Moshe Biton At the Weizmann Institute, in collaboration with Dr. Matan Khofri from the School of Engineering and Computer Science at the Hebrew University of Jerusalem, the scientists focused on the small intestinal epithelium, a tissue that lines the wall of the intestinal tube and is characterized by a constant and rapid turnover of cells that carry out a variety of functions – from food absorption and mucus secretion to immune defense. As part of an experiment in mice, the scientists examined what happens to the intestinal epithelium following infection with Salmonella, and observed that within 24 hours, the bacteria manage to invade a significant portion of the stem cells in the tissue that are responsible for its renewal, but instead of wreaking havoc and death, the cell turnover was faster than usual. Genomic sequencing at the single-cell level, which allows us to identify which genetic programs are expressed in each cell, revealed that stem cells infected with the bacteria tended to mature more than usual and turn into specific types of epithelial cells – cells with defense mechanisms against bacteria.
"We discovered that stem cells in the intestine accelerate their maturation when a bacterium invades them," describes Dr. Bitton. "Since these stem cells divide every day as a routine, their maturation ensures that those who are infected will not continue to reproduce. In effect, the infected stem cell 'sacrifices' its life and sentences itself to imminent death, in order to prevent prolonged infection and allow the remaining stem cells to restore the tissue. Another advantage of the mechanism we discovered is that the stem cells differentiate in a targeted manner into epithelial cells that can produce antibacterial substances, thus increasing their number in the tissue."
Until now, it seemed that stem cells in general, despite their importance, were unable to defend themselves against dangers, and were protected under the protective shell provided by the immune cells around them. However, maturation in response to infection was discovered to be an internal defense mechanism of stem cells, which also worked effectively in transgenic mice lacking a functioning immune system. In fact, the scientists found that each stem cell in the intestine has a system of protein clusters (inflammasomes) that act as "smoke detectors" to detect bacterial invasion. These "smoke detectors" also exist in cells of the innate immune system, but only in stem cells do they respond to invasion by activating an accelerated maturation program.
The scientists discovered that the new immune mechanism also works in miniature models of the human intestine grown in the lab and infected with Salmonella. In addition, they teamed up with Prof. Yael Haberman-Ziv of Sheba Medical Center and together identified a link between activation of the mechanism and specific bacterial infections common in patients with Crohn's disease.
"Inflammation is the body's response to a foreign or harmful factor - it helps tissues heal but can be destructive when it gets out of control and becomes chronic," explains Dr. Bitton. "We hypothesize that excessive differentiation of stem cells and their transformation into mature cells with immune activity against bacteria could be part of what causes excessive and chronic inflammation in Crohn's patients. Another possibility is that accelerated maturation is actually a result of the disease - Crohn's is accompanied by many more bacterial infections than usual and stem cells work overtime to deal with this. In any case, it is now clear that stem cell research is essential for understanding inflammatory diseases in humans."
Accelerated maturation of stem cells may in the future prove to be an effective defense mechanism not only against bacterial invasion, but also against other damage. It is possible that the "smoke detectors" in stem cells also detect genetic damage, inflammation, or metabolic disorders, triggering differentiation in response and inhibiting the division and reproduction of the damaged cell. In this way, the mechanism may shorten the life of a cell that has accumulated too many disruptions and prevent the development of diseases. "I hope that these discoveries will be able to advance the treatment of inflammatory diseases and cancer in the future," emphasizes Dr. Biton.
Also participating in the study were Aviya Habashosh Menachem, Dr. Natalia Davidson, Aviya Katz, Wladyslaw Holiar, Neta Blumberger and Dr. Dotan Hoffman from the Institute's Department of Immunology and Biological Regeneration; Dr. Noa Vigoda, Dr. Ron Rotkopf and Dr. Ina Goliand from the Institute's Department of Life Sciences Research Infrastructures; Tzipi Brown from Sheba Medical Center Tel Hashomer; Shira Liebhoff and Prof. Miriam Greenwald from the Hadassah Organoid Center; Dr. Diana Yahalomi, Dr. Meital Kuperwasser and Dr. Yishai Levin from the Nancy and Stephen Grand Israel National Center for Personalized Medicine at the Institute; Dr. Tali Dadosh, Dr. Smadar Levin-Zeidman and Dr. Nili Dzorla from the Institute's Department of Chemical Research Infrastructures.
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