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Nature. 2015 Dec 24;528(7583):560-564. doi: 10.1038/nature16460. Epub 2015 Dec 9.

Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration.

Author information

1
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
2
Department of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands.
3
Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York.
4
Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.
5
Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.
6
Department of Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York.
7
Department of Cancer Biology & Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York.
8
Department of Medicine, Baylor College of Medicine, Houston, Texas.
9
Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
10
Department of Medicine, Weill Cornell Medical College, New York, New York.
11
Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida.
#
Contributed equally

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.

PMID:
26649819
PMCID:
PMC4720437
DOI:
10.1038/nature16460
[Indexed for MEDLINE]
Free PMC Article

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