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通过肠干细胞分化的类器官模型筛选肠道上皮细胞组成的调节剂。

Screening for modulators of the cellular composition of gut epithelia via organoid models of intestinal stem cell differentiation.

机构信息

Harvard-MIT Program in Health Sciences and Technology, MIT, Cambridge, MA, USA.

Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.

出版信息

Nat Biomed Eng. 2022 Apr;6(4):476-494. doi: 10.1038/s41551-022-00863-9. Epub 2022 Mar 21.

DOI:10.1038/s41551-022-00863-9
PMID:35314801
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9046079/
Abstract

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.

摘要

屏障上皮细胞的细胞组成对于机体的动态平衡至关重要。特别是在小肠中，成体干细胞建立组织细胞数量，并且可能提供一种控制特化上皮细胞丰度和质量的方法。然而，缺乏鉴定调节上皮细胞组成和功能的生物学靶标以及调节它们的小分子的方法。在这里，我们通过使用数千个小型化的肠干细胞分化为 Paneth 细胞的类器官模型进行多重表型筛选，展示了鉴定肠干细胞分化的可成药生物学靶标和小分子调节剂的方法，并通过纵向单细胞 RNA 测序进行了验证。我们发现核输出蛋白 Exportin 1 的抑制剂可以调节肠干细胞的命运，而不依赖于已知的分化信号，这显著增加了类器官和野生型小鼠中 Paneth 细胞的丰度。肠干细胞分化的生理性类器官模型可能更广泛地用于筛选可以调节其他屏障上皮细胞组成和功能的生物学靶标和小分子。

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