Organoids for toxicology and genetic toxicology: applications with drugs and prospects for environmental carcinogenesis

Abstract

Advances in three-dimensional (3D) cell culture technology have led to the development of more biologically and physiologically relevant models to study organ development, disease, toxicology and drug screening. Organoids have been derived from many mammalian tissues, both normal and tumour, from adult stem cells and from pluripotent stem cells. Tissue organoids can retain many of the cell types and much of the structure and function of the organ of origin. Organoids derived from pluripotent stem cells display increased complexity compared with organoids derived from adult stem cells. It has been shown that organoids express many functional xenobiotic-metabolising enzymes including cytochrome P450s (CYPs). This has benefitted the drug development field in facilitating pre-clinical testing of more personalised treatments and in developing large toxicity and efficacy screens for a range of compounds. In the field of environmental and genetic toxicology, treatment of organoids with various compounds has generated responses that are close to those obtained in primary tissues and in vivo models, demonstrating the biological relevance of these in vitro multicellular 3D systems. Toxicological investigations of compounds in different tissue organoids have produced promising results indicating that organoids will refine future studies on the effects of environmental exposures and carcinogenic risk to humans. With further development and standardised procedures, advancing our understanding on the metabolic capabilities of organoids will help to validate their use to investigate the modes of action of environmental carcinogens.

Fig. 1.

Scheme showing the origin and application of organoid systems. Organoids can be derived from human and animal (e.g. mouse) pluripotent or adult stem cells. Normal and diseased organoids can be used for many applications such as disease modelling, organ development, drug screening, personalised medicine, toxicology and organ transplant and replacement.

Fig. 2.

Scheme of liver organoid culture formation from pluripotent stem cells or adult stem cells. On the top panel, pluripotent stem cells, embryonic or induced, undergo differentiation towards the desired cell type. PSCs are differentiated into hepatocytes and cholangiocytes which then generate organoid cultures containing both hepatocytes and bile duct cells. The bottom panel shows how organoids can be derived from minced adult tissue which contains Lgr5⁺ stem cells that in this case can give rise to liver organoid cultures containing ductal cells. Organoid cultures are embedded in basement membrane extract and are grown in media complemented with essential growth factors. Adapted from (66,119). An example of normal human adult liver organoids grown in our lab is shown on the right in the bottom panel.