Screening for modulators of the cellular composition of gut epithelia via organoid models of intestinal stem cell differentiation,Nature Biomedical Engineering

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Screening for modulators of the cellular composition of gut epithelia via organoid models of intestinal stem cell differentiation
Nature Biomedical Engineering ( IF 26.8 ) Pub Date : 2022-03-21 , DOI: 10.1038/s41551-022-00863-9
Benjamin E Mead _{1,

2,

3,

4,

5,

6,

7} , Kazuki Hattori _{2,

3,

8} , Lauren Levy _{2,

3,

8} , Shinya Imada ₂ , Norihiro Goto ₂ , Marko Vukovic _{1,

2,

3,

4,

5,

6,

7,

9} , Daphne Sze _{2,

3,

8} , Conner Kummerlowe _{2,

3,

4,

5,

7} , Juan D Matute _{10,

11} , Jinzhi Duan ₁₀ , Robert Langer _{1,

2,

5,

12} , Richard S Blumberg ₁₀ , Jose Ordovas-Montanes _{3,

4,

9} , Ömer H Yilmaz _{2,

13} , Jeffrey M Karp _{1,

3,

4,

8} , Alex K Shalek _{1,

2,

3,

4,

5,

6,

7}

Affiliation

Harvard-MIT Program in Health Sciences and Technology, MIT, Cambridge, MA, USA.
Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.
Harvard Stem Cell Institute, Cambridge, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Institute for Medical Engineering and Science, MIT, Cambridge, MA, USA.
Department of Chemistry, MIT, Cambridge, MA, USA.
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Division of Gastroenterology Boston Children's Hospital, Program in Immunology, Harvard Medical School, Boston, MA, USA.
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Division of Neonatology, Department of Pediatrics, MGH Harvard Medical School, Boston, MA, USA.
Department of Chemical Engineering, MIT, Cambridge, MA, USA.
Department of Pathology, MGH, Harvard Medical School, Boston, MA, USA.

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.

中文翻译：

通过肠干细胞分化的类器官模型筛选肠上皮细胞组成的调节剂

屏障上皮的细胞组成对于有机体的体内平衡至关重要。特别是，在小肠内，成体干细胞建立组织细胞结构，并可能提供控制特化上皮细胞的丰度和质量的方法。然而，缺乏识别调节上皮组成和功能的生物靶标以及调节它们的小分子的方法。在这里，我们表明，可以使用数千个肠道干细胞分化为潘氏细胞的小型类器官模型通过多重表型筛选来鉴定肠道干细胞分化的可药物生物靶点和小分子调节剂，并通过纵向单细胞RNA测序进行验证。我们发现核输出蛋白 Exportin 1 的抑制剂可以独立于已知的分化线索来调节肠道干细胞的命运，从而显着增加类器官和野生型小鼠中潘氏细胞的丰度。肠干细胞分化的生理类器官模型可以在筛选可以调节其他屏障上皮细胞的组成和功能的生物靶标和小分子方面找到更广泛的用途。

更新日期：2022-03-21

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