ArticleMolecular metabolism2020
ISX-9 manipulates endocrine progenitor fate revealing conserved intestinal lineages in mouse and human organoids.
Article in Molecular metabolism, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 37 citations in OpenAlex.
- Efficient control of enterochromaffin versus islet differentiation from human pluripotent stem cell-derived pancreatic progenitors.Nature communications · 2026Article
- Host response to bacteria induces a shift towards the enteroendocrine cell lineage in the murine enteroid model.PLoS pathogens · 2026Article
- ISX9 activates the Wnt/β-catenin signaling pathway and exerts neuroprotective effects in Alzheimer's disease.Alzheimer's research & therapy · 2026Article
- Enteroendocrine cell differentiation: Implications for human disease.Molecular and cellular endocrinology · 2025Review
- The IL-18 receptor is expressed on murine small-intestinal enterochromaffin cells and executes a recovery program upon injury.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The critical role of BMP signaling in gastric epithelial cell differentiation revealed by organoids.Cell regeneration (London, England) · 2025Article
- Measurement of Real-Time Serotonin Dynamics from Human-Derived Gut Organoids.Analytical chemistry · 2025Article
- A comprehensive cell atlas of fall armyworm (Spodoptera frugiperda) larval gut and fat body via snRNA-Seq.Scientific data · 2025Article
- LSD1 and CoREST2 Potentiate STAT3 Activity to Promote Enteroendocrine Cell Differentiation in Mucinous Colorectal Cancer.Cancer research · 2025Article
- A human stomach cell type transcriptome atlas.BMC biology · 2024Article
- ISX9 loaded thermoresponsive nanoparticles for hair follicle regrowth.Materials today. Bio · 2023Article
- Aryl hydrocarbon receptor utilises cellular zinc signals to maintain the gut epithelial barrier.Nature communications · 2023Article
- Applications of human organoids in the personalized treatment for digestive diseases.Signal transduction and targeted therapy · 2022Review
- Robust differentiation of human enteroendocrine cells from intestinal stem cells.Nature communications · 2022Article
- Targeting the Enteroendocrine System for Treatment of Obesity.Handbook of experimental pharmacology · 2022Article
- High Glucose Exposure Impairs L-Cell Differentiation in Intestinal Organoids: Molecular Mechanisms and Clinical Implications.International journal of molecular sciences · 2021Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveEnteroendocrine cells (EECs) survey the gut luminal environment and coordinate hormonal, immune and neuronal responses to it. They exhibit well-characterised physiological roles ranging from the control of local gut function to whole body metabolism, but little is known regarding the regulatory networks controlling their differentiation, especially in the human gut. The small molecule isoxazole-9 (ISX-9) has been shown to stimulate neuronal and pancreatic beta-cell differentiation, both closely related to EEC differentiation. Our aim was to use ISX-9 as a tool to explore EEC differentiation.
methodsWe investigated the effects of ISX-9 on EEC differentiation in mouse and human intestinal organoids, using real-time quantitative polymerase chain reaction (RT-qPCR), fluorescent-activated cell sorting, immunostaining and single-cell RNA sequencing.
resultsISX-9 increased the number of neurogenin3-RFP (Ngn3)-positive endocrine progenitor cells and upregulated NeuroD1 and Pax4, transcription factors that play roles in mouse EEC specification. Single-cell analysis showed induction of Pax4 expression in a developmentally late Ngn3+ population of cells and potentiation of genes associated with progenitors biased toward serotonin-producing enterochromaffin (EC) cells. Further, we observed enrichment of organoids with functional EC cells that was partly dependent on stimulation of calcium signalling in a population of cells residing outside the crypt base. Inducible Pax4 overexpression, in ileal organoids, uncovered its importance as a component of early human endocrine specification and highlighted the potential existence of two major endocrine lineages, the early appearing enterochromaffin lineage and the later developing peptidergic lineage which contains classical gut hormone cell types.
conclusionOur data provide proof-of-concept for the controlled manipulation of specific endocrine lineages with small molecules, whilst also shedding new light on human EEC differentiation and its similarity to the mouse. Given their diverse roles, understanding endocrine lineage plasticity and its control could have multiple therapeutic implications.
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