Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration.
Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration.
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DOI：
10.1038/nature16460
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发表时间：
2015-12-24
期刊：
影响因子：
64.8
通讯作者：
Hanash AM
中科院分区：
文献类型：
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作者：
Lindemans CA;Calafiore M;Mertelsmann AM;O'Connor MH;Dudakov JA;Jenq RR;Velardi E;Young LF;Smith OM;Lawrence G;Ivanov JA;Fu YY;Takashima S;Hua G;Martin ML;O'Rourke KP;Lo YH;Mokry M;Romera-Hernandez M;Cupedo T;Dow L;Nieuwenhuis EE;Shroyer NF;Liu C;Kolesnick R;van den Brink MRM;Hanash AM
肠损伤后，上皮再生对屏障的维持和器官功能至关重要。肠干细胞(ISC)生态位提供Wnt、Notch和表皮生长因子(EGF)信号，支持Lgr5+隐窝基柱状ISCs维持正常的上皮维持。然而，对组织损伤后ISC的调节知之甚少。利用体外器官培养，我们提供了证据表明，肠道损伤后产生白细胞介素22(IL-22)的天然淋巴细胞(ILCs)以IL-22依赖的方式促进小鼠小肠(SI)器官的生长。重组IL-22直接靶向ISCs，促进小鼠和人类肠道器官的生长，促进增殖，并促进ISC的扩张。IL-22可诱导Lgr5+ISCs中STAT3的磷酸化，STAT3在类器官形成和IL-22介导的再生中起关键作用。小鼠异基因骨髓移植(BMT)后体内应用IL-22可促进ISCs的恢复，增加上皮再生，降低肠道病理和移植物抗宿主病(GVHD)死亡率。Atoh1缺乏的类器官培养表明，IL-22诱导的上皮再生不依赖于Paneth细胞壁龛。我们的发现揭示了免疫系统能够支持肠道上皮、激活ISCs以促进再生的基本机制。
Epithelial regeneration is critical for barrier maintenance and organ function after intestinal injury. The intestinal stem cell (ISC) niche provides Wnt, Notch, and epidermal growth factor (EGF) signals supporting Lgr5+ crypt base columnar ISCs for normal epithelial maintenance. However, little is known about the regulation of the ISC compartment after tissue damage. Utilizing ex vivo organoid cultures, we provide evidence that innate lymphoid cells (ILCs), potent producers of Interleukin-22 (IL-22) after intestinal injury, increased the growth of murine small intestine (SI) organoids in an IL-22-dependent fashion. Recombinant IL-22 directly targeted ISCs, augmenting the growth of both murine and human intestinal organoids, increasing proliferation, and promoting ISC expansion. IL-22 induced Stat3 phosphorylation in Lgr5+ ISCs, and Stat3 was critical for both organoid formation and IL-22-mediated regeneration. Treatment with IL-22 in vivo after murine allogeneic bone marrow transplantation (BMT) enhanced recovery of ISCs, increased epithelial regeneration, and reduced intestinal pathology and mortality from graft vs. host disease (GVHD). Atoh1-deficient organoid culture demonstrated that IL-22 induced epithelial regeneration independent of the Paneth cell niche. Our findings reveal a fundamental mechanism by which the immune system is able to support intestinal epithelium, activating ISCs to promote regeneration.