Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche.
Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche.
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DOI：
10.1038/s41586-018-0257-1
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发表时间：
2018-07
期刊：
影响因子：
64.8
通讯作者：
Klein OD
中科院分区：
文献类型：
--
作者：
Nusse YM;Savage AK;Marangoni P;Rosendahl-Huber AKM;Landman TA;de Sauvage FJ;Locksley RM;Klein OD
上皮细胞表面形成与外界的关键屏障，并不断被成体干细胞更新。虽然上皮干细胞在体内平衡过程中的动力学越来越好地理解，但干细胞如何从组织维护程序中重新定向以启动损伤后的修复仍不清楚。在这里，我们研究了感染Heligmosomoides polygyrus（Hp），共同进化的病理共生体的小鼠，以评估上皮细胞的粘膜屏障破坏的反应。幽门螺杆菌通过穿透十二指肠粘膜破坏组织完整性，在那里它发展，同时被多细胞肉芽肿浸润所包围。出乎意料的是，肠干细胞（ISC）标志物，包括Lgr 5，失去了隐窝覆盖幼虫相关的肉芽肿，尽管持续上皮细胞增殖。肉芽肿相关的Lgr 5 −隐窝上皮激活了干扰素-γ（IFNγ）依赖的转录程序，Sca-1表达突出显示，在肉芽肿中发现了产生IFNγ的免疫细胞。类似的上皮反应伴随免疫细胞的全身激活、肠照射或Lgr 5 + ISCs的消融。肉芽肿相关的隐窝细胞在培养中产生胎儿样球体，而Hp诱导的细胞亚群激活了胎儿样转录程序，这表明成人肠道组织可以重新利用胎儿发育的各个方面。因此，发育程序的重新启动代表了肠隐窝在损伤后可以重塑以维持功能的基本机制。
Epithelial surfaces form critical barriers to the outside world and are continuously renewed by adult stem cells. Whereas epithelial stem cell dynamics 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 (Hp), a co-evolved pathosymbiont of mice, to assess the epithelial response to disruption of the mucosal barrier. Hp disrupts tissue integrity by penetrating the duodenal mucosa, where it develops while surrounded by a multicellular granulomatous infiltrate. Unexpectedly, intestinal stem cell (ISC) markers, including Lgr5, were lost in crypts overlying larvae-associated granulomas, despite continued epithelial proliferation. Granuloma-associated Lgr5− crypt epithelia activated an interferon-gamma (IFNγ)-dependent transcriptional program, highlighted by Sca-1 expression, and IFNγ-producing immune cells were found in granulomas. A similar epithelial response accompanied systemic activation of immune cells, intestinal irradiation, or ablation of Lgr5+ ISCs. Granuloma-associated crypt cells generated fetal-like spheroids in culture, and a sub-population of Hp-induced cells activated a fetal-like transcriptional program, demonstrating that adult intestinal tissues can repurpose aspects of fetal development. Thus, re-initiation of the developmental program represents a fundamental mechanism by which the intestinal crypt can remodel to sustain function after injury.
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影响因子：
64.8
作者：
Karin M;Clevers H
通讯作者：
Clevers H
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Metcalfe, Ciara;Kljavin, Noelyn M.;de Sauvage, Frederic J.
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de Sauvage, Frederic J.
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JARRETT, EEE
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8.8
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Garcia, Marie-Isabelle