Abstract
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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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.
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C.A.L. and M.C. designed and performed organoid experiments. A.M.M. and M.H.O. performed and analysed in vivo experiments. J.A.D., R.R.J. and E.V. provided input and helped with various assays. L.F.Y., O.M.S. and G.L. performed and monitored bone marrow transplants and maintained the mouse colonies. J.A.I. assisted with organoid quantification. Y.-Y.F. analysed crypt sizes and confocal microscopy. S.T. assisted with ILC co-culture experiments. G.H., M.L.M. and R.K. assisted with ISC isolation and in vivo ISC quantification experiments and provided reagents and expertise. K.P.O. and L.D. assisted with adeno-Cre experiments and optimizing various assays. Y.-H.L. and N.F.S. assisted with Paneth cell deficiency experiments. M.M. and E.E.N. performed the GSEA analyses and assisted with reagents and resources. M.R.-H. performed PCR analyses on purified stem cells and immune cells under the guidance of T.C., and C.L. analysed intestinal histopathology. M.R.M.vdB. and A.M.H. supervised the research. All authors contributed to experimental design, interpretation and manuscript editing.
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Extended data figures and tables
Extended Data Figure 1 IL-22 increases organoid growth without activating the Wnt or Notch pathways.
a, Microscopic tracing of organoid to measure surface area. b, Brightfield images of SI organoids from B6 mice, after 7 days of culture with/without IL-22 (5 ng ml−1). c–e, Organoid efficiency (percentage) relative to control (0 ng ml−1) for B6 SI organoids (statistics on data combined from n = 19 wells per group from 19 individual mice) (c), B6 large intestine organoids (n = 4 mice per group) cultured with/without rmIL-22 for 7 days (d), and human SI organoids cultured with/without rhIL-22 for 6 days (n = 3 donors per group) (e). f, RT–qPCR of relative mRNA expression of Wnt3, Ctnnb1 and Axin2 genes of the Wnt/β-catenin axis in SI organoids cultured with/without rmIL-22; n = 3 (0–1 ng ml−1) and n = 4 (5 ng ml−1) mice per group. g, Numbers of SI organoids per well with/without rmIL-22 (5 ng ml−1) in the presence or absence of R-spondin-1 (n = 6 wells per group). h, RT–qPCR-determined relative mRNA expression of Notch pathway genes (Hes1, Dll1 and Dll4; n = 8 mice per group) as well as of Slit2 and its receptor Robo1 (n = 3 mice per group) in day-7 SI organoids cultured with/without rmIL-22. i, Relative expression of Wnt3 and Axin2 (n = 3 mice per group), Hes1 (n = 5 mice per group), and Dll1 and Dll4 (n = 6 mice per group) genes in large intestine organoids. j, RT–qPCR for the relative mRNA expression of Reg3b and Reg3g innate antimicrobials in SI organoids cultured with rmIL-22; n = 3 (0–1 ng ml−1) and n = 4 (5 ng ml−1) mice per group. Organoid efficiency and number comparisons were performed with t-tests (two groups) or ANOVA (multiple groups). RT–qPCR statistics were performed with non-parametric Mann–Whitney U (two groups) or Kruskal–Wallis (multiple groups) tests. Data are mean and s.e.m.; *P < 0.05, ***P < 0.001. Data combined from at least two independent experiments unless otherwise stated.
Extended Data Figure 2 IL-22 activates STAT3 in intestinal organoids, and STAT3 deficiency leads to ISC gene signature loss in mice with colitis.
a, Intracellular staining of pSTAT3 (Y705) in organoid cells cultured under standard ENR conditions followed by a 20 min pulse of 20 ng ml−1 IL-22, evaluated by flow cytometry; data representative of two independent experiments. b, Brightfield images of SI organoids 4 days after crypt culture with/without Stattic; data representative of three experiments. c, SI organoids per well from wild-type and Stat1−/− mice with/without rmIL-22; n = 6 wells per group; ANOVA. d, e, Day 5 organoids from Stat3fl/fl SI crypt cells cultured with/without rmIL-22 (5 ng ml−1) in the absence of adeno-Cre infection; numbers per well (n = 6 wells per group) and size (n = 35 control and n = 42 IL-22-treated organoids per group), t-test (d); brightfield images representative of three experiments (e). f, g, GSEAs of the expression of a second independent ISC signature gene set (GSE36497) (f) and a negative control DLL1+CD24hi Paneth cell (PC) gene set (GSE39915) (g) in Stat3fl/fl;Villin-Cre− (wild type) versus Stat3fl/fl;Villin-Cre+ (Stat3ΔIEC) mice with DSS colitis, using GEO database array data (GSE15955). Each GSEA represents one analysis; nominal P values are shown. Data are mean and s.e.m.; ***P < 0.001. Data combined from at least two independent experiments unless otherwise stated.
Extended Data Figure 3 Efficiency of organoid formation from purified ISCs cultured with IL-22.
a, b, Organoid efficiency as percentage of plated cells, in organoid cultures from sorted Lgr5+ ISCs from B6 Lgr5–GFP reporter mice using a concentration of 1 ng ml−1 (n = 14 wells per group combined from three experiments; t-test) (a) and with a concentration range (one experiment, n = 3 wells per group; ANOVA) (b). Data are mean and s.e.m.; *P < 0.05.
Extended Data Figure 4 IL-22 increases cellular proliferation in intestinal organoids.
a, b, Confocal images (nuclear staining, blue; and EdU staining, red; one experiment) (a) and FACS analysis (b) of EdU incorporation (1 h) in SI organoids cultured in the presence or absence of rmIL-22 (1 ng ml−1); histogram representative of two experiments, graph shows paired t-test, n = 3 mice per group combined from two experiments. c, d, Cdkn1a and Cdkn2d mRNA expression (RT–qPCR) in organoids cultured from small (c) and large (d) intestine crypts for 24 h with 0, 3 or 6 h exposure to IL-22 before collection; Kruskal–Wallis analysis, n = 6 mice per group combined from two independent experiments. Data are mean and s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001.
Extended Data Figure 5 Intestinal organoids and crypts after irradiation.
a–c, Dissociated single cells from wild-type B6 crypts were exposed to escalating doses of irradiation ex vivo. a, b, Crypt cells were plated 3 h before irradiation, and cultures were treated with rmIL-22 (5 ng ml−1) added to the culture at 3 h before, 30 min before, 10 min after or 24 h after 4 Gy irradiation. Two days after irradiation, organoids were evaluated for MTT viability testing (percentage positive, n = 6 wells per group) (a) and the number of organoids generated (n = 6 wells per group) (b). c, The effect of IL-22 after irradiation was evaluated by measuring number of organoids 2 days and 7 days after irradiation (day 2: n = 9 wells per group for 1–2 Gy and n = 6 wells per group for 4 Gy; day 7: 4 Gy, n = 20 wells per group). Culture with/without IL-22 was initiated 3 h before irradiation. d, Small and large intestine crypt Il22ra1 expression determined by qPCR; RNA isolated from fresh crypts of B6 mice collected 1 day (20–26 h) after total body irradiation; n = 12 control and n = 11 irradiated mice per group. Comparisons performed with t-tests (two groups) or ANOVA (multiple groups). Data are mean and s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001. Data combined from at least two independent experiments.
Extended Data Figure 6 IL-22 treatment after allogeneic BMT.
B6 recipient mice were transplanted with only TCD bone marrow from LP donors, or with bone marrow and T cells from LP donors to induce GVHD (H-2b into H-2b). Mice receiving T cells were treated daily with PBS or 4 µg rmIL-22 by i.p. injection starting 7 days after BMT. a, Pathological scoring of apoptosis in intestinal tissues 3 weeks after BMT. Data from two experiments combined; n = 10 (TCD bone marrow only mice), n = 9 (BM + T (PBS)), n = 8 (BM + T (IL-22)); Kruskal–Wallis analysis. b, Representative haematoxylin and eosin staining of small and large intestines. Arrows indicate apoptotic cells within the intestinal epithelium. c, Splenocytes from recipients were analysed by flow cytometry 3 weeks after BMT, indicating frequencies of T cell subsets, expression of activation marker CD25, and expression of gut homing molecule α4β7 integrin; n = 9 (PBS-treated) and n = 10 (IL-22-treated) mice per group; t-test analysis. d, Expression of inflammatory cytokines in spleen (n = 9 PBS-treated and n = 10 IL-22-treated mice per group) and SI (n = 10 mice per group) was analysed in recipient tissues 3 weeks after BMT; t-test analyses, multiple comparisons corrected for with Holm–Sidak correction. e, REG3β immunohistochemistry staining in SI samples of recipient mice 3 weeks after BMT, data representative of three experiments. f–k, RT–qPCR of relative mRNA expression in SI tissue samples of PBS-treated versus IL-22-treated mice 3 weeks post-BMT for: Wnt3 (f); Egf (g); Hes1 (from purified crypts) (h); Rspo3 (i); Ctnnb1 (from purified crypts) (j); Axin2 (from purified crypts) (k); n = 10 mice per group for purified crypt samples; n = 8 (PBS-treated) and n = 9 (IL-22-treated) mice per group for whole SI tissue samples; Mann–Whitney U test. Data are mean and s.e.m.; *P < 0.05, **P < 0.01. Data combined from two independent experiments unless stated otherwise.
Extended Data Figure 7 IL-22 does not enhance Paneth cell frequency, Defa1 gene expression, or STAT3 phosphorylation in vitro.
a, Percentage of Paneth cells in organoids cultured with/without 5 ng ml−1 rmIL-22 for 7 days, as evaluated by flow cytometry after dissociation into single cells; n = 7 independent cultures per group (one mouse per culture); t-test. b, RT–qPCR analysis of the relative mRNA expression of Paneth cell gene Defa1 in SI organoids cultured with/without 5 ng ml−1 rmIL-22 for 7 days; n = 5 independent cultures per group (1–2 pooled mice per culture); Mann–Whitney U test. c–e, Paneth cell IL-22R expression and STAT3 phosphorylation assessed by flow cytometry. Shown are gating of Paneth cells based on side scatter and CD24 expression (c), Paneth cell IL-22R expression at baseline and 5 days after 1,200 cGy total body irradiation (one of two experiments) (d), and STAT3 phosphorylation in Paneth cells as determined by phosflow of dissociated crypt cells after a 20-min pulse with rmIL-22 (20 ng ml−1, 37 °C; one of two experiments) (e). Data are mean and s.e.m. Data combined from at least four independent experiments unless otherwise stated.
Extended Data Figure 8 ISCs express Il22ra1.
a, Relative mRNA expression of Il22ra1 in sorted Lgr5–GFP+ cells (n = 4 biological replicates), with various sorted haematopoietic populations serving as negative controls, including intestinal dendritic cells (n = 4), intestinal ILC3s (n = 2), and splenic B cells (n = 1). b, Lgr5 mRNA relative to Gapdh expression in sorted Lgr5–GFP+ cells and haematopoietic samples described above to confirm Lgr5 expression in sorted Lgr5–GFP+ cells. Data are mean and s.e.m.; Mann–Whitney U test; **P < 0.01.
Extended Data Figure 9 IL-22 increases the size of SI organoids cultured without EGF.
a, Efficiency of wild-type and Lgr5-DTR SI organoid formation after culture with diphtheria toxin (1 ng µl−1) to deplete Lgr5+ cells; one of three experiments; n = 6 (wild type), n = 5 (Lgr5-DTR), n = 6 (1 ng ml−1 IL-22), n = 6 (5 ng ml−1 IL-22) wells per group. b, Numbers of wild-type and Atoh1ΔIEC day-7 SI organoids cultured with/without rmIL-22 (5 ng ml−1); n = 6 wells per group. c, d, Omission of EGF from the standard ENR medium (NR). c, The effect of IL-22 on organoid numbers and size in the absence of EGF; n = 6 wells per group for numbers; n = 45 (ENR), n = 37 (ENR plus IL-22), n = 42 (NR), n = 54 (NR plus IL-22) organoids per group for size; data combined from three experiments. d, Brightfield images of wild-type SI organoid cultures in the presence or absence of EGF (50 ng ml−1), representative of three experiments. Data are mean and s.e.m. Comparisons were performed with t-tests (two groups) or ANOVA (multiple groups); *P < 0.05, **P < 0.01, ***P < 0.001. Data combined from three independent experiments unless otherwise stated.
Extended Data Figure 10 F-652 increases organoid size ex vivo and reduces radiation injury to the ISC compartment in vivo.
a, b, Area of small (a) and large (b) intestine wild-type B6 organoids cultured with/without the rhIL-22-dimer and Fc-fusion molecule F-652; SI: n = 37 (0 ng ml−1), n = 60 (0.1 ng ml−1), and n = 41 (1 ng ml−1) organoids per group combined from three experiments; LI: n = 137 (0 ng ml−1), n = 83 (0.1 ng ml−1) and n = 132 (1 ng ml−1) organoids per group combined from two experiments; ANOVA. c, d, Organoid efficiency relative to control in cultures of B6 SI organoids (n = 4 wells per group combined from two experiments) (c) and B6 LI organoids (n = 3 wells per group; one of two experiments) (d) treated with different concentrations of recombinant human F-652; ANOVA. e, f, B6 Lgr5-LacZ mice were treated with PBS or F-652 (100 µg kg−1), administered subcutaneously on the day of total body irradiation (10–12 Gy) and again 2 days later; one of three experiments. e, Lgr5-LacZ+ crypt cells per SI circumference were evaluated at day 3.5 after irradiation (10 Gy); statistics based on n = 11 independent sections (PBS-treated) versus n = 14 independent sections (F-652-treated) from irradiated mice; independent sections were derived from three mice per group; first dose of PBS or F-652 was administered 4 h before irradiation; Mann–Whitney U test. f, Representative crypt base images 3.5 days after irradiation (10 Gy). Arrows indicate Lgr5-LacZ+ crypt cells. Data are mean and s.e.m.; *P < 0.05, **P < 0.01.
Supplementary information
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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. (PDF 248 kb)
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Lindemans, C., Calafiore, M., Mertelsmann, A. et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 528, 560–564 (2015). https://doi.org/10.1038/nature16460
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DOI: https://doi.org/10.1038/nature16460
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