小柯机器人

研究揭示肠道类器官再生的表型特点
2020-10-10 13:59

瑞士巴塞尔大学Prisca Liberali及其研究组揭示了肠道类器官再生的表型特点。相关论文于2020年10月7日在线发表于国际学术期刊《自然》。

使用基于图像的筛选来分析已知的化合物文库,研究人员揭示了协调类器官形成和肠道组织再生的机制。研究人员描绘了成千上万个类器官的多元特征轮廓,以定量描述它们的表型。然后,利用这些表型图谱来推断调节性遗传相互作用,从而建立了一种新方法来映射新生系统中的遗传相互作用。这使得研究人员能够鉴定出调节细胞命运转变以及维持细胞再生和细胞稳态的基因,从而揭示了先前未知的几种途径的作用,其中包括视黄酸信号传导途径。

随后,研究人员验证了视黄酸核受体在调控再生状态终止和诱导肠上皮细胞分化中的关键作用。通过将定量成像与RNA测序相结合,研究人员揭示了内源性视黄酸代谢在调控肠上皮细胞命运转变转录程序中的作用,并且确定了类视黄醇X受体的抑制剂可改善体内肠上皮的再生。

据悉,在体外由单个成年肠道干细胞生成肠道类动物器官的现象印证了肠道上皮的再生能力。

附:英文原文

Title: Phenotypic landscape of intestinal organoid regeneration

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

Issue&Volume: 2020-10-07

Abstract: The development of intestinal organoids from single adult intestinal stem cells in vitro recapitulates the regenerative capacity of the intestinal epithelium1,2. 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.

DOI: 10.1038/s41586-020-2776-9

Source: https://www.nature.com/articles/s41586-020-2776-9

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

分享到:

0