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Phenotypic landscape of intestinal organoid regeneration

机译：肠道器有机体再生的表型景观

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摘要

The development of intestinal organoids from single adult intestinal stem cells in vitro recapitulates the regenerative capacity of the intestinal epithelium(1,2). Here we unravel the mechanisms that orchestrate both organoid formation and the regeneration of intestinal tissue, using an image-based screen to assay an annotated library of compounds. We generate multivariate feature profiles for hundreds of thousands of organoids to quantitatively describe their phenotypic landscape. We then use these phenotypic fingerprints to infer regulatory genetic interactions, establishing a new approach to the mapping of genetic interactions in an emergent system. This allows us to identify genes that regulate cell-fate transitions and maintain the balance between regeneration and homeostasis, unravelling previously unknown roles for several pathways, among them retinoic acid signalling. We then characterize a crucial role for retinoic acid nuclear receptors in controlling exit from the regenerative state and driving enterocyte differentiation. By combining quantitative imaging with RNA sequencing, we show the role of endogenous retinoic acid metabolism in initiating transcriptional programs that guide the cell-fate transitions of intestinal epithelium, and we identify an inhibitor of the retinoid X receptor that improves intestinal regeneration in vivo.An organoid-based screening platform maps the genetic interactions underlying intestinal development and regeneration, showing that retinoic acid metabolism maintains the balance between regeneration and homeostasis, and that an antagonist of the retinoid X receptor promotes regeneration in vivo.
机译：在体外从单个成人肠道干细胞的发展肠道有机体的发展概述了肠上皮的再生能力（1,2）。在这里，我们使用基于图像的屏幕来解开协调有机体形成和肠组织再生的机制来测定化合物的注释文库。我们为数十万个有机体产生多变量特征型材，以定量描述其表型景观。然后，我们使用这些表型指纹来推断出调节遗传相互作用，建立一种新的遗传交互映射的新方法。这使我们旨在鉴定调节细胞排气过渡的基因，并保持再生和稳态之间的平衡，揭开先前未知的几种途径的统一，其中视黄酸信号传导。然后，我们表征了视黄酸核受体控制从再生状态和促进肠细胞分化的关键作用。通过将定量成像与RNA测序相结合，我们展示了内源性视黄酸代谢在启动转录方案中的作用，引导肠上皮的细胞 - 命运过渡，并且我们鉴定了视黄醇X受体的抑制剂，从而改善了体内肠道再生。基于有机体的筛选平台地图潜在的肠道发育和再生的遗传相互作用，表明视黄酸代谢保持再生和稳态之间的平衡，并且类视黄醇X受体的拮抗剂促进体内再生。

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  • 来源
    《Nature》 |2020年第7828期|275-280|共6页
  • 作者

    Lukonin Ilya; Serra Denise; Challet Meylan Ludivine; Volkmann Katrin; Baaten Janine; Zhao Rui; Meeusen Shelly; Colman Karyn; Maurer Francisca; Stadler Michael B.; Jenkins Jeremy; Liberali Prisca;

  • 作者单位

    Friedrich Miescher Inst Biomed Res FMI Basel Switzerland|Univ Basel Basel Switzerland;

    Friedrich Miescher Inst Biomed Res FMI Basel Switzerland|Univ Basel Basel Switzerland;

    Friedrich Miescher Inst Biomed Res FMI Basel Switzerland;

    Friedrich Miescher Inst Biomed Res FMI Basel Switzerland;

    Novartis Res Fdn Genom Inst San Diego CA USA;

    Novartis Res Fdn Genom Inst San Diego CA USA;

    Novartis Res Fdn Genom Inst San Diego CA USA;

    Novartis Res Fdn Genom Inst San Diego CA USA;

    Friedrich Miescher Inst Biomed Res FMI Basel Switzerland;

    Friedrich Miescher Inst Biomed Res FMI Basel Switzerland|Swiss Inst Bioinformat Basel Switzerland;

    Novartis Inst Biomed Res Chem Biol & Therapeut CB Cambridge MA USA;

    Friedrich Miescher Inst Biomed Res FMI Basel Switzerland|Univ Basel Basel Switzerland;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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