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 - Funding Information:
Acknowledgements We gratefully acknowledge the technical assistance of the MSKCC Research Animal Resource Center and Molecular Cytology Core Facility. We also thank H. Clevers, H. Farin, S. Middendorp, C. Wiegerinck, J. van Es, M. van de Wetering, N. Sasaki, J. Sun and M. Li for their advice and critical evaluation of our work. This research was supported by National Institutes of Health award numbers K08-HL115355 (A.M.H.), R01-HL125571 (A.M.H.), R01-HL069929 (M.R.M.vdB.), R01-AI100288 (M.R.M.vdB.), R01-AI080455 (M.R.M.vdB.), R01-AI101406 (M.R.M.vdB.), P01-CA023766/Project 4 (R. J. O’Reilly/M.R.M.vdB.), K99-CA176376 (J.A.D.) and P30-CA008748 (MSKCC Core Grant). Support was also received from the US National Institute of Allergy and Infectious Diseases (NIAID contract HHSN272200900059C), the European Union (award GC220918, C. Blackburn), The Experimental Therapeutics Center of MSKCC funded by Mr William H. Goodwin and Mrs Alice Goodwin, The Lymphoma Foundation, Alex’s Lemonade Stand, The Geoffrey Beene Cancer Research Center at MSKCC, The Susan and Peter Solomon Divisional Genomics Program, MSKCC Cycle for Survival, and The Lucille Castori Center for Microbes, Inflammation & Cancer. T.C. was supported by Innovational Research Incentives Scheme Vidi grant 91710377 from the Netherlands Organization for Scientific Research (Zon-MW), and M.R.-H. was supported by the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7/2007-2013 under REA grant agreement no. 289720. A.M.M. was supported by the Bio Medical Exchange Program of the Deutscher Akademischer Austauschdienst. C.A.L. was supported by Dutch Cancer Society clinical fellowship grant 2013-5883 and by a mobility grant from the University Medical Center Utrecht. J.A.D. was supported by a C. J. Martin fellowship from the Australian National Health and Medical Research Council, a Scholar Award from the American Society of Hematology, and the Mechtild Harf Research Grant from the DKMS Foundation for Giving Life. A.M.H. was supported by a Scholar Award from the American Society of Hematology, a New Investigator Award from the American Society for Blood and Marrow Transplantation, and the Amy Strelzer Manasevit Research Program. A provisional patent application has been filed on the use of IL-22 and F-652 as ISC growth factors (US 61/901,151) with A.M.H., C.A.L. and M.R.M.vdB. listed as inventors.
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.
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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 -