PMID- 26649819
OWN - NLM
STAT- MEDLINE
DCOM- 20160201
LR  - 20231213
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 528
IP  - 7583
DP  - 2015 Dec 24
TI  - Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration.
PG  - 560-564
LID - 10.1038/nature16460 [doi]
AB  - 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.
FAU - Lindemans, Caroline A
AU  - Lindemans CA
AD  - Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New 
      York.
AD  - Department of Pediatrics, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Calafiore, Marco
AU  - Calafiore M
AD  - Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New 
      York.
FAU - Mertelsmann, Anna M
AU  - Mertelsmann AM
AD  - Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New 
      York.
FAU - O'Connor, Margaret H
AU  - O'Connor MH
AD  - Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New 
      York.
FAU - Dudakov, Jarrod A
AU  - Dudakov JA
AD  - Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New 
      York.
AD  - Department of Anatomy and Developmental Biology, Monash University, Clayton, 
      Australia.
FAU - Jenq, Robert R
AU  - Jenq RR
AD  - Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New 
      York.
FAU - Velardi, Enrico
AU  - Velardi E
AD  - Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New 
      York.
FAU - Young, Lauren F
AU  - Young LF
AD  - Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New 
      York.
FAU - Smith, Odette M
AU  - Smith OM
AD  - Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New 
      York.
FAU - Lawrence, Gillian
AU  - Lawrence G
AD  - Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New 
      York.
FAU - Ivanov, Juliet A
AU  - Ivanov JA
AD  - Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New 
      York.
FAU - Fu, Ya-Yuan
AU  - Fu YY
AD  - Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New 
      York.
FAU - Takashima, Shuichiro
AU  - Takashima S
AD  - Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New 
      York.
FAU - Hua, Guoqiang
AU  - Hua G
AD  - Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New 
      York, New York.
FAU - Martin, Maria L
AU  - Martin ML
AD  - Department of Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New 
      York, New York.
FAU - O'Rourke, Kevin P
AU  - O'Rourke KP
AD  - Department of Cancer Biology & Genetics, Memorial Sloan-Kettering Cancer Center, 
      New York, New York.
FAU - Lo, Yuan-Hung
AU  - Lo YH
AD  - Department of Medicine, Baylor College of Medicine, Houston, Texas.
FAU - Mokry, Michal
AU  - Mokry M
AD  - Department of Pediatrics, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Romera-Hernandez, Monica
AU  - Romera-Hernandez M
AD  - Department of Hematology, Erasmus University Medical Center, Rotterdam, the 
      Netherlands.
FAU - Cupedo, Tom
AU  - Cupedo T
AD  - Department of Hematology, Erasmus University Medical Center, Rotterdam, the 
      Netherlands.
FAU - Dow, Lukas
AU  - Dow L
AD  - Department of Medicine, Weill Cornell Medical College, New York, New York.
FAU - Nieuwenhuis, Edward E
AU  - Nieuwenhuis EE
AD  - Department of Pediatrics, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Shroyer, Noah F
AU  - Shroyer NF
AD  - Department of Medicine, Baylor College of Medicine, Houston, Texas.
FAU - Liu, Chen
AU  - Liu C
AD  - Department of Pathology, Immunology and Laboratory Medicine, University of 
      Florida College of Medicine, Gainesville, Florida.
FAU - Kolesnick, Richard
AU  - Kolesnick R
AD  - Department of Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New 
      York, New York.
FAU - van den Brink, Marcel R M
AU  - van den Brink MRM
AD  - Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New 
      York.
AD  - Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New 
      York.
FAU - Hanash, Alan M
AU  - Hanash AM
AD  - Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New 
      York.
LA  - eng
GR  - HHSN272200900059C/PHS HHS/United States
GR  - R01 AI101406/AI/NIAID NIH HHS/United States
GR  - HHSN272200900059C/AI/NIAID NIH HHS/United States
GR  - R01 HL069929/HL/NHLBI NIH HHS/United States
GR  - P01-CA023766/CA/NCI NIH HHS/United States
GR  - P01 CA023766/CA/NCI NIH HHS/United States
GR  - R01 CA142826/CA/NCI NIH HHS/United States
GR  - K22 CA181280/CA/NCI NIH HHS/United States
GR  - K99 CA176376/CA/NCI NIH HHS/United States
GR  - R01 AI080455/AI/NIAID NIH HHS/United States
GR  - K99-CA176376/CA/NCI NIH HHS/United States
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - U19 AI116497/AI/NIAID NIH HHS/United States
GR  - R01-HL125571/HL/NHLBI NIH HHS/United States
GR  - R01-AI100288/AI/NIAID NIH HHS/United States
GR  - R01 HL125571/HL/NHLBI NIH HHS/United States
GR  - R01-HL069929/HL/NHLBI NIH HHS/United States
GR  - R01 AI100288/AI/NIAID NIH HHS/United States
GR  - P30-CA008748/CA/NCI NIH HHS/United States
GR  - K08 HL115355/HL/NHLBI NIH HHS/United States
GR  - K08-HL115355/HL/NHLBI NIH HHS/United States
GR  - T32 GM007739/GM/NIGMS NIH HHS/United States
GR  - R01-AI101406/AI/NIAID NIH HHS/United States
GR  - R01-AI080455/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20151209
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Interleukins)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 0 (Stat3 protein, mouse)
SB  - IM
CIN - Nature. 2015 Dec 24;528(7583):488-9. doi: 10.1038/nature16325. PMID: 26649826
CIN - Nat Rev Gastroenterol Hepatol. 2016 Feb;13(2):64. doi: 10.1038/nrgastro.2015.221. 
      PMID: 26695084
MH  - Animals
MH  - Epithelial Cells/*cytology/immunology/pathology
MH  - Female
MH  - Graft vs Host Disease/pathology
MH  - Humans
MH  - Immunity, Mucosal
MH  - Interleukins/deficiency/*immunology
MH  - Intestinal Mucosa/*cytology/immunology/pathology
MH  - Intestine, Small/*cytology/immunology/pathology
MH  - Mice
MH  - Organoids/cytology/growth & development/immunology
MH  - Paneth Cells/cytology
MH  - Phosphorylation
MH  - *Regeneration
MH  - STAT3 Transcription Factor/metabolism
MH  - Signal Transduction
MH  - Stem Cell Niche
MH  - Stem Cells/*cytology/*metabolism
MH  - Interleukin-22
PMC - PMC4720437
MID - NIHMS739694
EDAT- 2015/12/10 06:00
MHDA- 2016/02/02 06:00
PMCR- 2016/06/09
CRDT- 2015/12/10 06:00
PHST- 2014/10/24 00:00 [received]
PHST- 2015/11/18 00:00 [accepted]
PHST- 2015/12/10 06:00 [entrez]
PHST- 2015/12/10 06:00 [pubmed]
PHST- 2016/02/02 06:00 [medline]
PHST- 2016/06/09 00:00 [pmc-release]
AID - 10.1038/nature16460 [doi]
PST - ppublish
SO  - Nature. 2015 Dec 24;528(7583):560-564. doi: 10.1038/nature16460. Epub 2015 Dec 9.