Insights Into Human Development and Disease From Human Pluripotent Stem Cell Derived Intestinal Organoids

Gastrointestinal symptoms in COVID-19 are associated with prolonged symptoms and increased severity. We employed human intestinal organoids derived from pluripotent stem cells (PSC-HIOs) to analyze SARS-CoV-2 pathogenesis and to validate efficacy of specific drugs in the gut. Certain, but not all cell types in PSC-HIOs express SARS-CoV-2 entry factors ACE2 and TMPRSS2, rendering them susceptible to SARS-CoV-2 infection. Remdesivir, a promising drug to treat COVID-19, effectively suppressed SARS-CoV-2 infection of PSC-HIOs. In contrast, the histamine-2-blocker famotidine showed no effect. Thus, PSC-HIOs provide an interesting platform to study SARS-CoV-2 infection and to identify or validate drugs.

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Human pluripotent stem cell–derived intestinal organoids with in vivo functionality

Science-Business eXchange ◽

10.1038/scibx.2014.1304 ◽

2014 ◽

Vol 7 (44) ◽

pp. 1304-1304

Keyword(s):

Stem Cell ◽

Pluripotent Stem Cell ◽

Human Pluripotent Stem Cell ◽

Intestinal Organoids

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Human Pluripotent Stem Cell-Derived Organoids as a Model of Intestinal Xenobiotic Metabolism

StemJournal ◽

10.3233/stj-200001 ◽

2020 ◽

pp. 1-10

Author(s):

Kengo Sasaki ◽

Makoto Inoue ◽

Masakazu Machida ◽

Tomoyuki Kawasaki ◽

Satoru Tsuruta ◽

...

Keyword(s):

Stem Cell ◽

Pluripotent Stem Cell ◽

Drug Transporters ◽

Oral Intake ◽

Human Pluripotent Stem Cell ◽

Catalytic Function ◽

Enzymatic Function ◽

Intestinal Organoids

Background: The human intestine is the site of absorption and first-pass metabolism for oral intake. Assessment of absorption, distribution, metabolism, excretion, and toxicity (ADMET) of xenobiotics has transformed the understanding of in vivo pharmacology. However, these processes are difficult torecapitulate in vitro. Objective: We have developed a simple protocol for the generation of mature functional intestinal organoids from human pluripotent stem cells (hPSCs)under xenogeneic-free conditions. We sought to characterize transcription level in drug transporters and metabolism and evaluate CYP3A4 catalytic function of the organoids. Methods: Human pluripotent stem cell-derived intestinal organoids were generated and evaluated the expression of drug transporters and metabolizing enzymes. We examined the induction of CYP3A4 and ABCB1 gene expression in the organoids. Furthermore, we analyzed the CYP3A4 enzyme activity of the organoids by the p450-Glo CYP3A4 assay kit with luciferin isopropyl acetal. Results: Stem cell-derived intestinal organoids had an outward polarized intestinal epithelial layer and showed similar expression levels of drug transporters and metabolism genes as the adult healthy intestine. They also exhibited CYP3A4 enzymatic function in vitro. Conclusion: This model provides a novel platform for pharmacological testing and can enhance human ADMET studies in drug development.

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