TY - JOUR
T1 - Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration
AU - Lindemans, Caroline A.
AU - Calafiore, Marco
AU - Mertelsmann, Anna M.
AU - O'Connor, Margaret H.
AU - Dudakov, Jarrod A.
AU - Jenq, Robert R.
AU - Velardi, Enrico
AU - Young, Lauren F.
AU - Smith, Odette M.
AU - Lawrence, Gillian
AU - Ivanov, Juliet A.
AU - Fu, Ya Yuan
AU - Takashima, Shuichiro
AU - Hua, Guoqiang
AU - Martin, Maria L.
AU - O'Rourke, Kevin P.
AU - Lo, Yuan Hung
AU - Mokry, Michal
AU - Romera-Hernandez, Monica
AU - Cupedo, Tom
AU - Dow, Lukas E.
AU - Nieuwenhuis, Edward E.
AU - Shroyer, Noah F.
AU - Liu, Chen
AU - Kolesnick, Richard
AU - Van Den Brink, Marcel R.M.
AU - Hanash, Alan M.
N1 - Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/12/24
Y1 - 2015/12/24
N2 - 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. Using ex vivo organoid cultures, here we show that innate lymphoid cells (ILCs), potent producers of interleukin-22 (IL-22) after intestinal injury, 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.
AB - 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. Using ex vivo organoid cultures, here we show that innate lymphoid cells (ILCs), potent producers of interleukin-22 (IL-22) after intestinal injury, 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.
UR - http://www.scopus.com/inward/record.url?scp=84951283991&partnerID=8YFLogxK
U2 - 10.1038/nature16460
DO - 10.1038/nature16460
M3 - Article
C2 - 26649819
AN - SCOPUS:84951283991
SN - 0028-0836
VL - 528
SP - 560
EP - 564
JO - Nature
JF - Nature
IS - 7583
ER -