Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration

被引：891

作者：

Lindemans, Caroline A. ^{[1
,2
]}

Calafiore, Marco ^{[1
]}

Mertelsmann, Anna M. ^{[1
]}

O'Connor, Margaret H. ^{[1
]}

Dudakov, Jarrod A. ^{[3
,4
]}

Jenq, Robert R. ^{[1
,5
]}

Velardi, Enrico ^{[3
]}

Young, Lauren F. ^{[3
]}

Smith, Odette M. ^{[3
]}

Lawrence, Gillian ^{[1
]}

Ivanov, Juliet A. ^{[1
]}

Fu, Ya-Yuan ^{[1
]}

Takashima, Shuichiro ^{[1
]}

Hua, Guoqiang ^{[6
,7
]}

Martin, Maria L. ^{[7
]}

O'Rourke, Kevin P. ^{[8
]}

Lo, Yuan-Hung ^{[9
]}

Mokry, Michal ^{[2
]}

Romera-Hernandez, Monica ^{[10
]}

Cupedo, Tom ^{[10
]}

Dow, Lukas E. ^{[5
]}

Nieuwenhuis, Edward E. ^{[2
]}

Shroyer, Noah F. ^{[9
]}

Liu, Chen ^{[11
]}

Kolesnick, Richard ^{[7
]}

van den Brink, Marcel R. M. ^{[1
,3
]}

Hanash, Alan M. ^{[1
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[2] Univ Med Ctr Utrecht, Dept Pediat, NL-3508 AB Utrecht, Netherlands

[3] Mem Sloan Kettering Canc Ctr, Dept Immunol, New York, NY 10065 USA

[4] Monash Univ, Dept Anat & Dev Biol, Clayton, Vic 3800, Australia

[5] Weill Cornell Med, Dept Med, New York, NY 10021 USA

[6] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10065 USA

[7] Mem Sloan Kettering Canc Ctr, Dept Mol Pharmacol, New York, NY 10065 USA

[8] Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10065 USA

[9] Baylor Coll Med, Dept Med, Houston, TX 77030 USA

[10] Erasmus Univ, Med Ctr, Dept Hematol, NL-3000 CA Rotterdam, Netherlands

[11] Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, Gainesville, FL 32610 USA

来源：

NATURE | 2015年 / 528卷 / 7583期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; INNATE LYMPHOID-CELLS; IN-VITRO; T-CELL; INFLAMMATION; EXPRESSION; NICHE; LGR5; INDUCTION;

D O I：

10.1038/nature16460

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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(1,2). However, little is known about the regulation of the ISC compartment after tissue damage. Using ex vivo organoid cultures, here we show that innate lymphoid cells (ILCs), potent producers of interleukin-22 (IL-22) after intestinal injury(3,4), increase the growth of mouse small intestine organoids in an IL-22-dependent fashion. Recombinant IL-22 directly targeted ISCs, augmenting the growth of both mouse and human intestinal organoids, increasing proliferation and promoting ISC expansion. IL-22 induced STAT3 phosphorylation in Lgr5(+) ISCs, and STAT3 was crucial for both organoid formation and IL-22-mediated regeneration. Treatment with IL-22 in vivo after mouse allogeneic bone marrow transplantation enhanced the recovery of ISCs, increased epithelial regeneration and reduced intestinal pathology and mortality from graft-versus-host disease. ATOH1-deficient organoid culture demonstrated that IL-22 induced epithelial regeneration independently of the Paneth cell niche. Our findings reveal a fundamental mechanism by which the immune system is able to support the intestinal epithelium, activating ISCs to promote regeneration.

引用

页码：560 / +

页数：18

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