Engineering functional human gastrointestinal organoid tissues using the three primary germ layers separately derived from pluripotent stem cells

Abstract

The development of human organoid model systems has provided new avenues for patient-specific clinical care and disease modeling. However, all organoid systems are missing important cell types that, in the embryo, get incorporated into organ tissues during development. Based on the concept of how embryonic organs are assembled, we developed an organoid assembly approach starting with cells from the three primary germ layers; enteric neuroglial, mesenchymal, and epithelial precursors, all separately derived from human pluripotent stem cells. From these we generated human gastric tissue containing differentiated glands, surrounded by layers of smooth muscle containing functional enteric neurons that controlled contractions of the engineered tissue. We used this highly tractable system to identify essential roles for the enteric nervous system in the growth and regional identity of the gastric epithelium and mesenchyme and for glandular morphogenesis of the antral stomach. This approach of starting with separately-derived germ layer components was applied to building more complex fundic and esophageal tissue, suggesting this as a new paradigm for tissue engineering.

Stem Cells, Helicobacter pylori, and Mutational Landscape: Utility of Preclinical Models to Understand Carcinogenesis and to Direct Management of Gastric Cancer

“…65,127 Such cultures require a stepwise differentiation protocol, first guiding the pluripotent cells to differentiate into the desired tissue by recapitulating embryo-fetal development. 128,129 Organoids derived from healthy tissue represent an authentic model to study mouse and human gastric tissue behavior in vitro, as it mimics tissue architecture, polarization, and differentiation, and allows observations on nontransformed cells. 130 As they are amenable to genetic manipulation (eg, by CRISPR/Cas), healthy normal organoids can be used to model and functionally analyze the effect of specific mutations.…”