PSC-derived intestinal organoids with apical-out orientation as a tool to study nutrient uptake, drug absorption and metabolism

Panagiota Kakni; Carmen López-Iglesias; Roman Truckenmüller; Pamela Habibović; Stefan Giselbrecht

doi:10.3389/fmolb.2023.1102209

PSC-derived intestinal organoids with apical-out orientation as a tool to study nutrient uptake, drug absorption and metabolism

Front Mol Biosci. 2023 Jan 18:10:1102209. doi: 10.3389/fmolb.2023.1102209. eCollection 2023.

Authors

Panagiota Kakni¹, Carmen López-Iglesias², Roman Truckenmüller¹, Pamela Habibović¹, Stefan Giselbrecht¹

Affiliations

¹ MERLN Institute for Technology-Inspired Regenerative Medicine, Department of Instructive Biomaterials Engineering, Maastricht University, Maastricht, Netherlands.
² Microscopy CORE lab, Maastricht Multimodal Molecular Imaging Institute (M4I), Maastricht University, Maastricht, Netherlands.

Abstract

Intestinal organoids recapitulate many features of the in vivo gastrointestinal tract and have revolutionized in vitro studies of intestinal function and disease. However, the restricted accessibility of the apical surface of the organoids facing the central lumen (apical-in) limits studies related to nutrient uptake and drug absorption and metabolism. Here, we demonstrate that pluripotent stem cell (PSC)-derived intestinal organoids with reversed epithelial polarity (apical-out) can successfully recapitulate tissue-specific functions. In particular, these apical-out organoids show strong epithelial barrier formation with all the major junctional complexes, nutrient transport and active lipid metabolism. Furthermore, the organoids express drug-metabolizing enzymes and relevant apical and basolateral transporters. The scalable and robust generation of functional, apical-out intestinal organoids lays the foundation for a completely new range of organoid-based high-throughput/high-content in vitro applications in the fields of nutrition, metabolism and drug discovery.

Keywords: barrier integrity; drug discovery; epithelial polarity; gastrointestinal model; intestinal organoids; nutrient uptake.

Grants and funding

This study was financially supported by the Dutch Province of Limburg (program “Limburg INvesteert in haar Kenniseconomie/LINK”; SAS-2014–00837 and SAS-2018–02477). The authors gratefully acknowledge the Gravitation Program “Materials Driven Regeneration”, funded by the Netherlands Organization for Scientific Research (024.003.013).