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The differentiation state of small intestinal organoid models influences prediction of drug-induced toxicity

ABSTRACT: Drug-induced intestinal toxicity (GIT) is a frequent dose-limiting adverse event that can impact patient compliance and treatment outcomes. In vivo, there are proliferative and differentiated cell types critical to maintaining intestinal homeostasis. Traditional in vitro models using transformed cell lines do not capture this cellular complexity, and often fail to predict intestinal toxicity. Primary tissue-derived intestinal organoids, on the other hand, are a scalable Complex in vitro Model (CIVM) that recapitulates major intestinal cell lineages and function. Intestinal organoid toxicity assays have been shown to correlate with clinical incidence of drug-induced diarrhea, however existing studies do not consider how differentiation state of the organoids impact assay readouts and predictivity. We employed distinct proliferative and differentiated organoid models of the small intestine to assess whether differentiation state alone can alter toxicity responses to small molecule compounds in cell viability assays. In doing so, we identified several examples of small molecules which elicit differential toxicity in proliferative and differentiated organoid models. This proof of concept highlights the need to consider which cell types are present in CIVMs, their differentiation state, and how this alters interpretation of toxicity assays.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277613 | GEO | 2025/01/23

REPOSITORIES: GEO

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Project description:Human intestinal epithelial organoids (IEO) culture models are rapidly emerging as novel experimental tools to investigate fundamental aspects of intestinal epithelial (patho)physiology. Cellular source and culture protocols vary between different IEO models and reliable markers for their characterization/validation are currently limited. DNA methylation has been demonstrated to play a key role in regulating gene expression and cellular function. This epigenetic mark is comparably stable and has been shown to reflect cellular identity such as tissue origin, developmental stage and age. Our genome wide DNA methylation datasets of purified human epithelium represent a unique resource, which can be used by other researchers to validate their model systems We provide the following datasets of genome-wide DNA methylation profiling by Infinium HumanMethylation450 BeadChip: Purified intestinal epithelial cells (EpCAM+) from paediatric ileum and colon, Non-epithelial mucosal cells (EpCAM-), Whole colonic mucosal biopsies, Intestinal organoid cultures from paediatric ileum and colon, Purified intestinal epithelial cells (EpCAM+) from foetal small intestine and foetal large intestine, Intestinal organoid cultures from foetal small intestine and foetal large intestine, Intestinal organoid cultures derived from induced pluripotent stem cells. Note: Some samples in this data set were previously submitted to ArrayExpress under accession number E-MTAB-3709. They're clearly marked in the âDescriptionâ field in sample annotations. Information about batch effect during sample handling is included in the experimental variable âblockâ. Batch effect is not massive but present, so it is recommended that batch correction is carried out in data analysis. Complementary RNA-seq data on the purified cells and organoids can be found in ArrayExpress at E-MTAB-5015 ( https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-5015/ ).

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The differentiation state of small intestinal organoid models influences prediction of drug-induced toxicity

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