Modeling Gastrointestinal Diseases Using Organoids to Understand Healing and Regenerative Processes

Abstract

The gastrointestinal tract is a continuous series of organs from the mouth to the esophagus, stomach, intestine and anus that allows digestion to occur. These organs are frequently associated with chronic stress and injury during life, subjecting these tissues to frequent regeneration and to the risk of developing disease-associated cancers. The possibility of generating human 3D culture systems, named organoids, that resemble histologically and functionally specific organs, has opened up potential applications in the analysis of the cellular and molecular mechanisms involved in epithelial wound healing and regenerative therapy. Here, we review how during normal development homeostasis takes place, and the role of the microenvironmental niche cells in the intestinal stem cell crypt as an example. Then, we introduce the notion of a perturbed niche during disease conditions affecting the esophageal-stomach junction and the colon, and describe the potential applications of organoid models in the analysis of human gastrointestinal disease mechanisms. Finally, we highlight the perspectives of organoid-based regenerative therapy to improve the repair of the epithelial barrier.

Keywords: disease-modeling; epithelial–mesenchymal crosstalk; gastrointestinal tract; homeostasis; inflammatory bowel diseases; metaplasia; niche; organoid.

Figure 1

From fetal to adult stage: development of the intestinal stem cell niche. (A). At fetal age, the epithelium is pseudostratified and composed of cells expressing the stem cell marker LGR5. (B). At adult age, crypts and villi form and are surrounded by gradients of secreted molecules.

Figure 2

A metaplasic condition: the Barret’s esophagus. A transition zone exists between the stratified squamous epithelium of the esophagus and the glandular epithelium of the stomach. Under acid reflux, a metaplasia occurs and intestinal goblet cells are abnormally found in the epithelium.

Figure 3

Organoid culture to understand the evolution of normal epithelia toward dysplasia and into neoplasia. Organoids can be derived from the esophagus, stomach and intestinal tissues from diseased or normal conditions. Mimicking disease states in culture could be considered by acidifying the culture media to mimic acid reflux in Barret’s esophagus, colonizing the gastric organoid with H. pylori or adding a pro-inflammatory cytokine cocktail to reproduce a Crohn’s disease condition. Co-culture of diseased organoids with stromal components could help decipher mechanisms involved in the repaired phase.