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 maintenance1,2. 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 injury3,4, 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.
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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.
Extended data figures
Supplementary Figure 1 shows the original uncropped images of western blots presented in Figures 2 and 4 and Supplementary Table 1 shows a list of antibodies used to perform flow cytometry, western blotting, and tissue staining for immunohistochemistry and immunofluorescence.
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Cell Death & Disease (2019)