Related Experiment Video
Updated: Mar 10, 2026
Author Spotlight: Generation and Manipulation of Rat Intestinal Organoids
Published on: June 23, 2023
Characterization of stem cell-derived liver and intestinal organoids as a model system to study nuclear receptor
Ingrid T G W Bijsmans1, Alexandra Milona1, Noortje Ijssennagger1
1Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
Abstract:
Nuclear receptors (NRs) are ligand-activated transcription factors regulating a large variety of processes involved in reproduction, development, and metabolism. NRs are ideal drug targets because they are activated by lipophilic ligands that easily pass cell membranes. Immortalized cell lines recapitulate NR biology poorly and generating primary cultures is laborious and requires a constant need for donor material. There is a clear need for development of novel preclinical model systems that better resemble human physiology. Uncertainty due to technical limitations early in drug development is often the cause of preclinical drugs not reaching the clinic. Here, we studied whether organoids, mini-organs derived from the respective mouse tissue's stem cells, can serve as a novel model system to study NR biology and targetability. We characterized mRNA expression profiles of the NR superfamily in mouse liver, ileum, and colon organoids. Tissue-specific expression patterns were largely maintained in the organoids, indicating their suitability for NR research. Metabolic NRs Fxrα, Lxrα, Lxrβ, Pparα, and Pparγ induced expression of and binding to endogenous target genes. Transcriptome analyses of wildtype colon organoids stimulated with Rosiglitazone showed that lipid metabolism was the highest significant changed function, greatly mimicking the PPARs and Rosiglitazone function in vivo. Finally, using organoids we identify Trpm6, Slc26a3, Ang1, and Rnase4, as novel Fxr target genes. Our results demonstrate that organoids represent a framework to study NR biology that can be further expanded to human organoids to improve preclinical testing of novel drugs that target this pharmacologically important class of ligand activated transcription factors.
Insights
Mouse organoids effectively model nuclear receptor (NR) biology and drug targeting. These mini-organs maintain tissue-specific gene expression and accurately mimic in vivo responses to metabolic NR activators, identifying novel drug targets.
Area of Science:
- Pharmacology
- Genomics
- Developmental Biology
Background:
- Nuclear receptors (NRs) are crucial transcription factors for metabolism and development, making them key drug targets.
- Current preclinical models like cell lines and primary cultures poorly recapitulate NR biology and human physiology.
- There is a significant need for advanced model systems to improve early drug development and reduce clinical attrition.
Purpose of the Study:
- To investigate the utility of mouse organoids as a novel preclinical model system for studying NR biology and targetability.
- To characterize the expression of the NR superfamily within mouse liver, ileum, and colon organoids.
- To assess the functional response of organoids to metabolic NR activators and identify novel NR target genes.
Main Methods:
- Cultured mouse liver, ileum, and colon organoids derived from stem cells.
- Performed mRNA expression profiling of the NR superfamily in organoids.
- Stimulated wildtype colon organoids with Rosiglitazone and conducted transcriptome analysis.
- Validated NR target gene induction and binding in organoids.
Main Results:
- Organoids successfully maintained tissue-specific NR expression patterns, confirming their suitability for NR research.
- Metabolic NRs (Fxrα, Lxrα/β, Pparα/γ) demonstrated functional activity by inducing target gene expression and binding.
- Rosiglitazone treatment in colon organoids significantly altered lipid metabolism pathways, mirroring in vivo PPAR activity.
- Identified Trpm6, Slc26a3, Ang1, and Rnase4 as novel Fxr target genes within organoid models.
Conclusions:
- Mouse organoids serve as a robust framework for studying NR biology and drug target validation.
- Organoid models accurately recapitulate NR-mediated physiological responses, offering a more predictive preclinical system.
- Expansion to human organoids holds promise for enhancing the preclinical testing of drugs targeting NRs.
