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The small intestine is a place of birth and migration. Every day, hundreds of millions of new cells (more than in any other tissue) are born at bottoms of the villi –tiny finger-like projections on the inner intestinal wall. The newborn cells migrate along the surface of the villi for just four days before being shed from their tips. Now researchers at the Weizmann Institute of Science have discovered that this busy scene is even more dynamic than previously thought.
The migrating cells are produced from stem cells in crypt-like crevices between the villi. Until now, scientists believed that once these cells differentiated into different cell types, this differentiation was final – that is, once a stem cell matured into, say, an enterocyte, the most common cell type in the inner intestinal wall, its transformation was over. But in the new study, reported in Cell, the Weizmann scientists showed that as the enterocytes migrate along the surfaces of the villi, they continue to differentiate, fulfilling different functions at different locations – like workers moving along an assembly line to perform different tasks at each work station.
Postdoctoral fellow Dr. Andreas E. Moor and members of the team led by Prof. Shalev Itzkovitz in the Molecular Cell Biology Department showed that the changing roles played by the enterocytes are perfectly suited to each location. At the bottom of the villi, the enterocytes act as gatekeepers, secreting antibacterial proteins. “It makes sense for this function to be fulfilled at the base of the villi,” explains Itzkovitz. “At this location, the antibacterial substances prevent harmful bacteria from entering the crypts between the villi, where the crucial renewal of the intestinal wall is taking place.”
The absorption of different nutrients also turned out to occur at different locations on the villi. The gatekeeper enterocytes at the bottom were found to specialize in absorbing amino acids. Around the middle of the villi, the enterocytes transform into a different subtype that specializes in absorbing glucose. Finally, at the tips of the villi, the enterocytes differentiate into yet another subtype that specializes in absorbing fats. “They are all still called enterocytes, but we’ve shown that each subtype acquires such distinct characteristics that they are really different types of cell,” Itzkovitz says.
The cells at the tips of the villi were shown to perform yet another crucial function. They absorb organic complexes called ATP which are released into the intestinal cavity in large amounts by bacteria populating the gut. If these ATPs weren’t taken up and neutralized by the enterocytes, they could be perceived by the body as a danger signal, prompting it to launch an immune attack. “The enterocytes at the tips of the villi appear to be important for maintaining a balanced immune response to the microbes in the intestines,” says Itzkovitz.
Each subtype acquires such distinct characteristics that they are really different types of cell
To characterize the enterocytes from different parts of the villi – which all told measure about half a millimeter in length – the scientists used a method called laser capture, which provided them with cell samples from each spot. They sequenced the messenger RNA molecules from these cells to determine which genes are expressed at each location, and they identified so-called landmark genes – ones that are most characteristic of each location. They then sequenced the genomes of thousands of single cells and used the landmark genes to localize these cells along the villus, thereby creating a high-resolution map of the expression of all enterocyte genes.
The sequencing revealed that nearly 85% of the enterocyte genes were expressed differently by location – their expression increased or decreased as the cells moved along the villi. The research team – which included Yotam Harnik, Shani Ben-Moshe, Efi E. Massasa, Milena Rozenberg, Dr. Raya Eilam and Dr. Keren Bahar Halpern – then characterized groups of genes expressed at different locations. They found, for example, that certain genes expressed at the tips of the villi produce signaling molecules that perform potent anti-inflammatory functions in the intestine.
The methods developed by the research team can be applied to creating detailed atlases of cells in various body tissues, as well as in tumors. They also open up new possibilities for investigating disease: for example, checking whether gene expression that doesn’t match cell location in the inner wall of the small intestine could be involved in inflammatory bowel diseases.
Prof. Shalev Itzkovitz's research is supported by the Wolfson Family Charitable Trust; the Edmond de Rothschild Foundations; and the European Research Council.