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Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche

机译：寄生性蠕虫在肠道干细胞小生境中诱导胎儿样逆转

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摘要

Epithelial surfaces form critical barriers to the outside world and are continuously renewed by adult stem cells(1). Whereas dynamics of epithelial stem cells during homeostasis are increasingly well understood, how stem cells are redirected from a tissue-maintenance program to initiate repair after injury remains unclear. Here we examined infection by Heligmosomoides polygyrus, a co-evolved pathosymbiont of mice, to assess the epithelial response to disruption of the mucosal barrier. H. polygyrus disrupts tissue integrity by penetrating the duodenal mucosa, where it develops while surrounded by a multicellular granulomatous infiltrate(2). Crypts overlying larvae-associated granulomas did not express intestinal stem cell markers, including Lgr5(3), in spite of continued epithelial proliferation. Granuloma-associated Lgr5(-) crypt epithelium activated an interferon-gamma (IFN-gamma)-dependent transcriptional program, highlighted by Sca-1 expression, and IFN-gamma-producing immune cells were found in granulomas. A similar epithelial response accompanied systemic activation of immune cells, intestinal irradiation, or ablation of Lgr5(+) intestinal stem cells. When cultured in vitro, granuloma-associated crypt cells formed spheroids similar to those formed by fetal epithelium, and a sub-population of H. polygyrus-induced cells activated a fetal-like transcriptional program, demonstrating that adult intestinal tissues can repurpose aspects of fetal development. Therefore, re-initiation of the developmental program represents a fundamental mechanism by which the intestinal crypt can remodel itself to sustain function after injury.
机译：上皮表面形成了对外界的重要屏障，并被成年干细胞不断更新（1）。尽管人们越来越了解动态平衡过程中上皮干细胞的动力学，但尚不清楚如何将干细胞从组织维护程序重定向到损伤后开始修复。在这里，我们检查了Heligmosomoides polygyrus（一种共同进化的小鼠共生体）的感染情况，以评估对粘膜屏障破坏的上皮反应。 polygyrus穿透了十二指肠粘膜破坏了组织的完整性，在被多细胞肉芽肿浸润物包围的同时发展（2）。尽管上皮细胞持续增殖，但是覆盖幼虫相关肉芽肿的土窖不表达肠道干细胞标记物，包括Lgr5（3）。肉芽肿相关的Lgr5（-）隐窝上皮激活了干扰素-γ（IFN-γ）依赖的转录程序，突出了Sca-1表达，并且在肉芽肿中发现了产生IFN-γ的免疫细胞。相似的上皮反应伴随着免疫细胞的全身活化，肠辐射或Lgr5（+）肠干细胞的消融。在体外培养时，与肉芽肿相关的隐窝细胞形成的球状体与胎儿上皮形成的球状体相似，并且由多回H.polygyrus诱导的细胞亚群激活了胎儿样的转录程序，表明成年肠道组织可以改变胎儿的用途。发展。因此，发育程序的重新启动代表了一种基本机制，肠隐窝可以通过该机制重塑自身以在受伤后维持功能。

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  • 来源
    《Nature》 |2018年第7712期|109-113|共5页
  • 作者

    Nusse Ysbrand M.; Savage Adam K.; Marangoni Pauline; Rosendahl-Huber Axel K. M.; Landman Tyler A.; de Sauvage Frederic J.; Locksley Richard M.; Klein Ophir D.;

  • 作者单位

    Univ Calif San Francisco, Biomed Sci Grad Program, San Francisco, CA 94143 USA;

    Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA;

    Univ Calif San Francisco, Program Craniofacial Biol, San Francisco, CA 94143 USA;

    Univ Calif San Francisco, Program Craniofacial Biol, San Francisco, CA 94143 USA;

    Univ Calif San Francisco, Program Craniofacial Biol, San Francisco, CA 94143 USA;

    Genentech Inc, Dept Mol Oncol, San Francisco, CA USA;

    Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA;

    Univ Calif San Francisco, Program Craniofacial Biol, San Francisco, CA 94143 USA;

  • 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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