Researchers review the latest discoveries from studies of tissue-derived and pluripotent stem cell–derived intestinal, gastric, esophageal, liver, and pancreatic organoids in the May issue of Gastroenterology. Studies of organoids have provided valuable information about GI development, tissue homeostasis, and disease and might be used to develop personalized medicines.
In vitro organoid cultures are generated from stem or progenitor cells and provide useful research tools due to their long-term growth, cellular diversity, function, and spatial organization specific to the organ they represent. They have been used to study endoderm-derived GI organs, and allow for growth of diverse primary human tissues in vitro.
Priya H. Dedhia et al explain that before the development of human GI organoids, digestive diseases were modeled using cell lines and explanted tissue, which have many limitations. Advances in maintaining GI tissues in long-term in vitro cultures have allowed researchers to overcome these barriers.
In their review, the authors describe the various long-term in vitro GI models that have been created and how these have increased our understanding of development, genetic diseases of the GI tract, malignancy, host-pathogen interactions, tissue reprogramming, and regeneration.
Dedhia et al discuss liver organoids that differentiate toward hepatocytes and pluripotent stem cell-derived liver buds that can rescue mice from rescuing drug-induced liver failure. Furthermore, pancreatic epithelial organoids can be generated from embryonic or adult progenitors that arise after injury. Pancreatic epithelial organoids generated from mouse embryonic tissue give rise to acinar and endocrine structures in vitro.
GI organoids generated from human specimens provide a valuable adjunct to mouse developmental studies and can be used to study developmental events that are difficult to study in vivo. Transplantation of pluripotent stem cell-derived organoids into mice resulted in the maturation of these fetal-like tissues into tissues resembling those of adults, characterized by prominent crypt-villus structures and expression of markers of mature small intestine.
The review describes organoids the have been used to model human genetic diseases, infections, inflammatory bowel diseases (IBD), and malignancies. For example, epithelial organoids have been used to study the CFTR and mutations associated with cystic fibrosis. They can also serve as models for microvillus inclusion disease (MIA), multiple intestinal atresia, and enteric anendocrinosis—an extremely rare disease caused by mutations in NEUROG3 and characterized by severe malabsorptive diarrhea and a lack of intestinal enteroendocrine cells.
Organoids grown from intestinal tissues of patients with IBD have been used to study cell death, mucosal integrity, and inflammation in this disease. They have also been used to study defects in Paneth cell function, which have been associated with susceptibility to Crohn’s disease, and the roles of oxidative stress in pathogenesis of IBD.
These organoids are also important for analyzing the pathogenesis of microbial infections. For example, gastric organoids infected with Helicobacter pylori, but not with variants that lack its virulence factor, CagA, increase proliferation and their gene expression signatures have been analyzed.
Intestinal organoids are important models of infection with bacteria such as Salmonella or Clostridium difficile, intestinal barrier function, and to possible treatments. They have also provide important information about development of necrotizing enterocolitis.
Organoids from mouse colon and human small intestine and colon have been used study the genetic changes that transform epithelial cells into adenocarcinomas. Epithelial organoids from mouse colon and human small intestine and colon, and generated from intestinal adenomas of APC-deficient mice, have been used to study Wnt signaling during cancer development. And CRISPR-Cas9 genome editing can been used to alter expression of tumor suppressor genes and oncogenes in colon epithelial organoids grown from normal human colon tissues.
Human colonic organoids generated from adenocarcinomas and normal tissues can be used to therapeutic agents for those most likely to have effects in individual patients. Dedhia et al propose that organoids be used in high-throughput screens of drugs and pharmacologic agents for those with specific effects in certain patients.
Finally, the review authors provide a thorough discussion of how long-term organotypic cultures can be used to study the stem cell niche and as guides for normal development and sources of replacement tissues and in gut regeneration.