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Engineering Functional Stomach Tissue Organoids

Researchers continue to expand the types of tissue that can be produced in small amounts to form organoids, lacking the integrated blood vessel network needed to support larger sections, but otherwise at least partially functional. This stage of development in the tissue engineering field offers considerable benefits, both as a way to speed up research with a cheaper alternative to animal studies, but also the potential for transplantation. Even small tissue patches can be an effective therapy for some conditions: the tissue will integrate with the body, and blood vessels will grow in to support it. For organs that are essentially chemical factories or filters, such as the kidney and liver, transplant of numerous functional organoids grown from a patient's own cells may well prove to be good enough to address a number of presently incurable degenerative conditions. Here, researchers demonstrate construction of stomach tissue organoids:

Scientists report using pluripotent stem cells to generate human stomach tissues in a petri dish that produce acid and digestive enzymes. Researchers grew tissues from the stomach's corpus/fundus region. The study comes two years after the same team generated the stomach's hormone-producing region (the antrum). The discovery means investigators now can grow both parts of the human stomach to study disease, model new treatments and understand human development and health in ways never before possible. "Now that we can grow both antral- and corpus/fundic-type human gastric mini-organs, it's possible to study how these human gastric tissues interact physiologically, respond differently to infection, injury and react to pharmacologic treatments." The current study caps a series of discoveries since 2010 in which research teams used human pluripotent stem cells (hPSC) - which can become any cell type in the body - to engineer regions of the human stomach and intestines. They are using the tissues to identify causes and treatments for diseases of the human gastrointestinal tract. This includes a study in which scientists generated human intestine with an enteric nervous system. These highly functional tissues are able to absorb nutrients and demonstrate peristalsis, the intestinal muscular contractions that move food from one end of the GI tract to the other.

A major challenge investigators encountered in the current study is a lack of basic knowledge on how the stomach normally forms during embryonic development. "We couldn't engineer human stomach tissue in a petri dish until we first identified how the stomach normally forms in the embryo." To fill that gap, the researchers used mice to study the genetics behind embryonic development of the stomach. In doing so, they discovered that a fundamental genetic pathway (WNT/β-catenin) plays an essential role in directing development of the corpus/fundus region of the stomach in mouse embryos. After this, researchers manipulated the WNT/β-catenin in a petri dish to trigger the formation of human fundus organoids from pluripotent stem cells. The team then further refined the process, identifying additional molecular signaling pathways that drive formation of critical stomach cell types of the fundus. These include chief cells, which produce a key digestive enzyme called pepsin, and parietal cells. Parietal cells secrete hydrochloric acid for digestion and intrinsic factor to help the intestines absorb vitamin B-12, which is critical for making blood cells and maintaining a healthy nervous system. It takes about six weeks for stem cells to form gastric-fundus tissues in a petri dish. Researchers now plan to study the ability of tissue-engineered human stomach organoids to model human gastric diseases by transplanting them into mouse models.

Link: https://www.cincinnatichildrens.org/news/release/2017/stem-cells-generate-human-stomach

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