Interleukin-22 Promotes Intestinal-stem-cell-mediated Epithelial Regeneration

Overview

Journal Nature

Specialty Science

Date 2015 Dec 10

PMID 26649819

Citations 551

Authors

Caroline A Lindemans

Marco Calafiore

Anna M Mertelsmann

Margaret H OConnor

Jarrod A Dudakov

Robert R Jenq

Enrico Velardi

Lauren F Young

Odette M Smith

Gillian Lawrence

Juliet A Ivanov

Ya-Yuan Fu

Shuichiro Takashima

Guoqiang Hua

Maria L Martin

Kevin P ORourke

Yuan-Hung Lo

Michal Mokry

Monica Romera-Hernandez

Tom Cupedo

Lukas Dow

Edward E Nieuwenhuis

Noah F Shroyer

Chen Liu

Richard Kolesnick

Marcel R M van den Brink

Alan M Hanash

Affiliations

Soon will be listed here.

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.

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