Tweaking hormone-producing cells in the intestine

Did you ever wonder where that sudden feeling of hunger comes from when your empty stomach rumbles? Thousands of nutrient-sensitive cells, or enteroendocrine cells, scattered throughout your stomach and intestine just released millions of tiny vesicles filled with the hunger hormone ghrelin into your bloodstream. Such hormones act as the gut's primary method of communication and coordination with more distant parts of the digestive tract or other organs such as the pancreas and the brain. In response to certain stimuli, different enteroendocrine cells produce different hormones, which induce hunger or satiety, coordinate movement of intestinal muscles, stimulate the repair of the intestine's protective cell layer or promote a higher output of insulin from the pancreas. The latter is especially interesting in patients with type II diabetes, which are on their own unable to produce sufficient insulin to stabilize their glucose levels. One of the most successful treatments for diabetes is based on the gut hormone GLP1, with which these patients are able to control their blood glucose without the need of insulin injections.

Less than 1% of the cells in the intestinal lining are enteroendocrine cells. This 1% is again split into many different subtypes that produce different hormones. Therefore, a specific type of enteroendocrine cell is hard to find. It's like looking for a few diamonds, rubies, and emeralds in a truck-load of pebbles. You can weigh the load, measure it, grind it down and analyze the mineral composition, but this will tell you a lot more about the pebbles than about the gemstones.

To study these rare cells, the researchers combined a technology called single-cell sequencing (see framed explanation of single-cells sequencing), to look at each individual cell, with a method to determine the age of each cell. To stay with the gemstone analogy, they made all gemstones shine so brightly that they could be picked out from the pile and analyzed individually. In addition, the color of the gemstones told the researchers how old each one was. As a result, they could study the development of enteroendocrine cells.

Enteroendocrine cells are continuously produced in our intestines and live for several weeks. Surprisingly, the researchers found that many enteroendocrine cells change their hormone production while they were aging. This ability of a cell to switch their hormone production and thus their function is highly interesting in the context of therapy. Once we understand the signals that control it, we may be able to stimulate the intestine to increase the production of specific hormones to treat diabetes, obesity or inflammatory bowel disease. The researchers already showed that manipulation of one of these signals could change hormone levels, including those of GLP1, in mice.

Single-cell sequencing is a relatively new technology that was chosen as "Breakthrough of the year 2018" by the scientific journal Science. Using this technique, researchers can read the activity of genes at the resolution of individual cells. This tells them what genetic program was active in a cell, and by derivation what its identity was (for instance a skin cell or an immune cell). Researchers were already able to read gene activity in a tissue, but these readouts were always done on many thousands of cells pooled together. Now, with single-cell sequencing, researchers are able to read the gene activity of every individual cell. We can compare this improvement to moving from a classical geographical map, where a city is represented as one patch of one color, to Google Maps, where we can zoom into every house individually, finding rare and interesting houses in the process.

Since the technique can be applied to many different research fields, many researchers are now looking to it to analyze their organ or disease of interest at single-cell resolution. However, performing single-cell sequencing, and interpreting its results requires highly specialized lab equipment and data analysis algorithms. To solve this issue, a startup called Single Cell Discoveries was created at the Hubrecht Insitute that performs single-cell sequencing as a service to researchers and clinical institutions around the world.

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Hans Clevers is group leader at the Hubrecht Institute (KNAW), professor of Molecular Genetics at the University Medical Center Utrecht and Utrecht University, Research Director of the Princess Máxima Center for Pediatric Oncology and Oncode Investigator.

This research is a collaboration between researchers at the Hubrecht Institute, the Princess Máxima Center for Pediatric Oncology, the University Medical Center in Utrecht, The Netherlands, the Wellcome Trust-MRC Institute of Metabolic Science in Cambridge, UK, and the Allen Institute for Brain Science in Seattle, USA.