Screening for modulators of the cellular composition of gut epithelia via organoid models of intestinal stem cell differentiation
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s41551-022-00863-9.pdf
Description
Published version
Size
16.79 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Mead, Benjamin E
Hattori, Kazuki
Levy, Lauren
Imada, Shinya
Goto, Norihiro
Vukovic, Marko
Sze, Daphne
Kummerlowe, Conner
Matute, Juan D
Duan, Jinzhi
Date Issued
2022
Journal
Nature Biomedical Engineering
Publisher
Springer Science and Business Media LLC
Citation
Mead, Benjamin E, Hattori, Kazuki, Levy, Lauren, Imada, Shinya, Goto, Norihiro et al. 2022. "Screening for modulators of the cellular composition of gut epithelia via organoid models of intestinal stem cell differentiation." Nature Biomedical Engineering, 6 (4).
Version
Final published version
Abstract
AbstractThe cellular composition of barrier epithelia is essential to organismal homoeostasis. In particular, within the small intestine, adult stem cells establish tissue cellularity, and may provide a means to control the abundance and quality of specialized epithelial cells. Yet, methods for the identification of biological targets regulating epithelial composition and function, and of small molecules modulating them, are lacking. Here we show that druggable biological targets and small-molecule regulators of intestinal stem cell differentiation can be identified via multiplexed phenotypic screening using thousands of miniaturized organoid models of intestinal stem cell differentiation into Paneth cells, and validated via longitudinal single-cell RNA-sequencing. We found that inhibitors of the nuclear exporter Exportin 1 modulate the fate of intestinal stem cells, independently of known differentiation cues, significantly increasing the abundance of Paneth cells in the organoids and in wild-type mice. Physiological organoid models of the differentiation of intestinal stem cells could find broader utility for the screening of biological targets and small molecules that can modulate the composition and function of other barrier epithelia.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/S41551-022-00863-9
