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.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.|Department of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Lindemans
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Marco
authors.initials: M
authors.lastname: Calafiore
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Mertelsmann
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Margaret H
authors.initials: MH
authors.lastname: O'Connor
authors.affiliation: Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York.|Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Dudakov
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Jenq
authors.affiliation: Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Enrico
authors.initials: E
authors.lastname: Velardi
authors.affiliation: Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Lauren F
authors.initials: LF
authors.lastname: Young
authors.affiliation: Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Odette M
authors.initials: OM
authors.lastname: Smith
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Gillian
authors.initials: G
authors.lastname: Lawrence
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Juliet A
authors.initials: JA
authors.lastname: Ivanov
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Ya-Yuan
authors.initials: YY
authors.lastname: Fu
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Takashima
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Hua
authors.affiliation: Department of Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Martin
authors.affiliation: Department of Cancer Biology & Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: O'Rourke
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Yuan-Hung
authors.initials: YH
authors.lastname: Lo
authors.affiliation: Department of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Michal
authors.initials: M
authors.lastname: Mokry
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Monica
authors.initials: M
authors.lastname: Romera-Hernandez
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Cupedo
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Lukas
authors.initials: L
authors.lastname: Dow
authors.affiliation: Department of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Nieuwenhuis
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Noah F
authors.initials: NF
authors.lastname: Shroyer
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Richard
authors.initials: R
authors.lastname: Kolesnick
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.|Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Marcel R M
authors.initials: MRM
authors.lastname: van den Brink
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Hanash
mesh_terms: D000818:Animals; D004847:Epithelial Cells / Q000166:cytology* / Q000276:immunology / Q000473:pathology; D005260:Female; D006086:Graft vs Host Disease / Q000473:pathology; D006801:Humans; D018928:Immunity, Mucosal; D007378:Interleukins / Q000172:deficiency / Q000276:immunology*; D007413:Intestinal Mucosa / Q000166:cytology* / Q000276:immunology / Q000473:pathology; D007421:Intestine, Small / Q000166:cytology* / Q000276:immunology / Q000473:pathology; D051379:Mice; D009940:Organoids / Q000166:cytology / Q000254:growth & development / Q000276:immunology; D019879:Paneth Cells / Q000166:cytology; D010766:Phosphorylation; D012038:Regeneration; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D055153:Stem Cell Niche; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse