Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration Journal Article
| Authors: | Lindemans, C. A.; Calafiore, M.; Mertelsmann, A. M.; O'Connor, M. H.; Dudakov, J. A.; Jenq, R. R.; Velardi, E.; Young, L. F.; Smith, O. M.; Lawrence, G.; Ivanov, J. A.; Fu, Y. Y.; Takashima, S.; Hua, G.; Martin, M. L.; O'Rourke, K. P.; Lo, Y. H.; Mokry, M.; Romera-Hernandez, M.; Cupedo, T.; Dow, L. E.; Nieuwenhuis, E. E.; Shroyer, N. F.; Liu, C.; Kolesnick, R.; van den Brink, M. R. M.; Hanash, A. M. |
| Article Title: | Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration |
| 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 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. © 2015 Macmillan Publishers Limited. All rights reserved. |
| Keywords: | protein phosphorylation; nonhuman; flow cytometry; stat1 protein; stat3 protein; apoptosis; gene expression; allogenic bone marrow transplantation; graft versus host reaction; intestine epithelium cell; cell regeneration; immunofluorescence test; beta catenin; wnt protein; stem cell niche; interleukin 22; diphtheria toxin; intestine injury; intracellular signaling; lymphoid cell; paneth cell; lamina propria; intestinal stem cell; priority journal; article; slit2 protein; epithelial regeneration |
| Journal Title: | Nature |
| Volume: | 528 |
| Issue: | 7583 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2015-12-24 |
| Start Page: | 560 |
| End Page: | 564 |
| Language: | English |
| DOI: | 10.1038/nature16460 |
| PROVIDER: | scopus |
| PMCID: | PMC4720437 |
| PUBMED: | 26649819 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 February 2016 -- Source: Scopus |
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