[1S06e] 15. Advanced Cell and Cell Culture Engineering for Biopharmaceuticals and Functional Food - Part 3

4:30 PM - 5:00 PM JST(7:30 AM - 8:00 AM UTC)

[1ACCE-11-KL] Human Organoids as Next-Generation Models: Advanced Platforms for Nutrient and Drug Metabolism

○Yu Takahashi¹ (1. Graduate School of Agricultural and Life Sciences, The University of Tokyo (Japan))

Keywords:

Organoid,Intestinal epithelium,Hepatocyte,Nutrient metabolism,Drug screening

Organoids, miniaturized organ models, offer a revolutionary alternative to animal models and conventional cell lines, delivering superior physiological relevance for nutrition and food science. With the cosmetics and food industries increasingly banning animal testing due to welfare concerns, the demand for human-relevant alternatives has never been more urgent. Traditional rodent models exhibit species differences in metabolic systems, such as muricholic acid production, which is absent in humans, and resistance to atherosclerosis under high-fat diet feeding. Moreover, human cancer-derived cell lines, such as Caco-2 (intestinal epithelium model) and HepG2 (hepatocyte model) cells, exhibit chromosomal abnormalities and lack the expression of critical xenobiotic-metabolizing enzymes, such as cytochrome P450 (CYP) families, showing unphysiological aspects of nutrient and drug metabolism. Although human organoids hold promise for offering new solutions to unresolved questions in human biology, they face challenges such as high culture costs and complicated handling. Therefore, we first worked on building a platform that enables researchers to conveniently use organoids as routine experimental materials. Focusing on the small intestine and liver, organs crucial for evaluating nutrient and drug absorption and metabolism, we decided to work with human small intestinal and liver organoids. Consequently, we established stable cell lines expressing multiple growth factors simultaneously and at an optimal expression balance using a lentiviral expression system. The use of culture supernatant from these cells for organoid proliferation achieved a significant cost reduction. Furthermore, we developed a method for highly efficient gene transduction into organoids through transient two-dimensional culture and for efficiently differentiating induced pluripotent stem cells into each organoid type. We also succeeded in creating monolayer epithelial cells from small intestinal organoids with the luminal side exposed, enabling stimulation from the inner luminal surface. We found that these cells exhibit physiological functions that cannot be replicated using conventional models, including CYP induction, glucose absorption, and very low-density lipoprotein and chylomicron secretion. In addition, by leveraging these foundational technologies, we screened compounds from a library of compounds with known pharmacological activities. We successfully identified compounds across multiple themes that could not be identified without organoids. In this presentation, I will outline our achievements over approximately ten years of organoid research and discuss the prospects of utilizing organoids in next-generation basic research.