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
Notes: Article -- Export Date: 3 February 2016 -- Source: Scopus
Citation Impact
MSK Authors
  1. Alan M Hanash
    106 Hanash
  2. Jarrod Andrew Dudakov
    58 Dudakov
  3. Robert R Jenq
    107 Jenq
  4. Richard N Kolesnick
    286 Kolesnick
  5. Guoqiang Hua
    18 Hua
  6. Enrico Velardi
    44 Velardi
  7. Odette Marsinay Smith
    98 Smith
  8. Lauren Young
    39 Young
  9. Maria Laura Martin
    14 Martin
  10. Juliet   Ivanov
    3 Ivanov
  11. Ya-Yuan   Fu
    10 Fu