Building additional complexity to in vitro-derived intestinal tissues

Gastrointestinal (GI) disorders affect up to 25% of the US population. Common intestinal disorders include malabsorption, irritable bowel syndrome and fecal incontinence. Some GI disorders such as Hirschsprung's disease have a genetic basis and are associated with an absence or paucity of enteric nerves. Current treatment plans for GI disorders range from changes in diet to bowel resection, and there are very few drugs available that target the primary deficiencies in intestinal function such as controlled peristalsis. While animal models can recapitulate the broad range of intestinal pathologies of the GI tract, they are intrinsically complicated and of low throughput. Several in vitro systems have been established, and these range from epithelial enteroids to more complex organoids, which contain most intestinal cell types. One of the more complex organoid systems was derived from adult mouse intestines and contains functional enteric nerves and smooth muscle capable of peristalsis. Establishing an equivalent human intestinal system is challenging due to limited access and variable quality of human intestinal tissues. However, owing to recent advances, it is possible to differentiate human induced and embryonic pluripotent stem cells, collectively called pluripotent stem cells, into human intestinal organoids (HIOs) in vitro. Although HIOs contain a significant degree of epithelial and mesenchymal complexity, they lack enteric nerves and thus are unable to model the peristaltic movements of the gut. The goal of this review is to discuss approaches to generate complex in vitro systems that can be used to more comprehensively model common intestinal pathologies. New and more biologically complete human models of the intestine would allow for unprecedented studies of the cellular and molecular basis of normal and pathological gut function. Furthermore, fully functional HIOs could serve as a platform for preclinical drug studies to model absorption and efficacy.