The promise of human organoids in the digestive system

Abstract

The advent of organoid technology has enabled scientists and clinicians to utilize cells from primary tissues or pluripotent stem cells (PSCs) to grow self-organizing tissue systems, thus attaining cellular diversity, spatial organization, and functionality as found within digestive tracts. The development of human gastrointestinal (GI) and hepato-biliary-pancreatic organoids as an in-a-dish model present novel opportunities to study humanistic mechanisms of organogenesis, regeneration and pathogenesis. Herein, we review the recent portfolios of primary tissue-derived and PSC-derived organoids in the digestive systems. We also discuss the promise and challenges in disease modeling and drug development applications for digestive disorders.

Fig. 1. Principles of developmental biology to generate digestive organoids.

a Overview of digestive organ formation. b Development of PSC-derived digestive organoids. a Endoderm cell lineages projected on to a schematic of the digestive organs. As development proceeds, broad gene expression patterns within the foregut, midgut, and hindgut become progressively refined into precise domains in which specific organs will form. The foregut gives rise to the esophagus, stomach, liver, and pancreas; whereas the midgut forms the small intestine and the hindgut forms the large intestine. b PSCs [embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs)] can be derived into the endoderm in vitro with specific stepwise differentiation protocols. After the endoderm specification, progenitor cells are transferred into 3D systems and generate digestive organoids with developmental signals.

Fig. 2. Personalized medicine application using digestive organoids.

Establishment of the individual patient tissue-derived digestive organoid biobank and in vitro drug testing using clinically relevant assay (e.g., FIS assay using rectal organoids for Cystic fibrosis) for personalized medicine approaches.

Fig. 3. Digestive organoid-based phenotypic drug discovery and development pipelines.

Patient-derived digestive organoids can be used in phenotypic screening and subsequent in vitro preclinical studies (e.g., toxicology testing) for drug discovery and development. 3D phenotypic assay technologies, including organs/bodies-on-a-chip using microfluidic devices, will play a prominent role in hit validation and profiling. As the organoid-based strategies mature, preclinical animal experiments can be phased out.

Fig. 4. Different platforms for generating digestive organoids.

Foregut-derived spheroids from PSCs do not merely generate epithelial cell types but also co-differentiate mesenchymal cell components, which may possess a capability to become supportive lineages such as hepatic stellate cells and Kupffer cells, thus can be used for inflammatory disease modeling, while AdSC-derived digestive organoids include no mesenchymal cell component, thus co-culture system with mesenchymal cells is required.