类有机物
干细胞
细胞生物学
生物
细胞分化
潘尼斯电池
小肠
肠上皮
电池类型
细胞
肠粘膜
地穴
上皮
生物化学
遗传学
基因
内分泌学
内科学
医学
作者
Benjamin E. Mead,Kazuki Hattori,Lauren Levy,Shinya Imada,Norihiro Goto,Marko Vukovic,Daphne Sze,Conner Kummerlowe,Juan D. Matute,Jinzhi Duan,Robert Langer,Richard S. Blumberg,José Ordovás-Montañés,Ömer H. Yılmaz,Jeffrey M. Karp,Alex K. Shalek
标识
DOI:10.1038/s41551-022-00863-9
摘要
The 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.
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