Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration
Innate lymphoid cells increase the growth of mouse intestinal organoids via IL-22 production; recombinant IL-22 promotes growth of both mouse and human organoids, and promotes mouse intestinal stem cell (ISC) expansion and ISC-driven organoid growth via a STAT3-dependent pathway and independently of...
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| Veröffentlicht in: | Nature (London) 2015-12, Vol.528 (7583), p.560-564 |
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| creator | Lindemans, Caroline A. Calafiore, Marco Mertelsmann, Anna M. O’Connor, Margaret H. Dudakov, Jarrod A. Jenq, Robert R. Velardi, Enrico Young, Lauren F. Smith, Odette M. Lawrence, Gillian Ivanov, Juliet A. Fu, Ya-Yuan Takashima, Shuichiro Hua, Guoqiang Martin, Maria L. O’Rourke, Kevin P. Lo, Yuan-Hung Mokry, Michal Romera-Hernandez, Monica Cupedo, Tom Dow, Lukas E. Nieuwenhuis, Edward E. Shroyer, Noah F. Liu, Chen Kolesnick, Richard van den Brink, Marcel R. M. Hanash, Alan M. |
| description | Innate lymphoid cells increase the growth of mouse intestinal organoids via IL-22 production; recombinant IL-22 promotes growth of both mouse and human organoids, and promotes mouse intestinal stem cell (ISC) expansion and ISC-driven organoid growth via a STAT3-dependent pathway and independently of Paneth cells; IL-22 treatment in vivo enhances the recovery of ISCs from intestinal injury.
Intestinal repair mechanisms
The cellular signals supporting normal epithelial intestine maintenance through regulation of intestinal stem cell (ISC) activity are well characterized, but the signals involved in the regulation of the ISC compartment after damage are still unclear. Alan Hanash and colleagues have found that innate lymphoid cells produce interleukin-22 (IL-22) after injury to increase the growth of mouse intestinal organoids. They further show that recombinant IL-22 promotes ISC expansion in both human and mouse organoids, via a STAT3-dependent pathway and independently of the Paneth cells, which provide for ISC maintenance signals. IL-22 treatment also enhanced the recovery of ISCs from intestinal injury.
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
1
,
2
. 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
3
,
4
, 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 |
| doi_str_mv | 10.1038/nature16460 |
| format | Article |
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Intestinal repair mechanisms
The cellular signals supporting normal epithelial intestine maintenance through regulation of intestinal stem cell (ISC) activity are well characterized, but the signals involved in the regulation of the ISC compartment after damage are still unclear. Alan Hanash and colleagues have found that innate lymphoid cells produce interleukin-22 (IL-22) after injury to increase the growth of mouse intestinal organoids. They further show that recombinant IL-22 promotes ISC expansion in both human and mouse organoids, via a STAT3-dependent pathway and independently of the Paneth cells, which provide for ISC maintenance signals. IL-22 treatment also enhanced the recovery of ISCs from intestinal injury.
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
1
,
2
. 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
3
,
4
, 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.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/nature16460</identifier><identifier>PMID: 26649819</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/250/127/1213 ; 631/250/1904 ; 631/250/347 ; 631/532/2437 ; Animals ; Bone marrow ; Cell cycle ; Cytokines ; Epidermal growth factor ; Epithelial cells ; Epithelial Cells - cytology ; Epithelial Cells - immunology ; Epithelial Cells - pathology ; Female ; Gene expression ; Graft vs Host Disease - pathology ; Health aspects ; Humanities and Social Sciences ; Humans ; Immune system ; Immunity, Mucosal ; Interleukin-22 ; Interleukins ; Interleukins - deficiency ; Interleukins - immunology ; Intestinal Mucosa - cytology ; Intestinal Mucosa - immunology ; Intestinal Mucosa - pathology ; Intestine, Small - cytology ; Intestine, Small - immunology ; Intestine, Small - pathology ; Large intestine ; letter ; Mice ; multidisciplinary ; Organoids - cytology ; Organoids - growth & development ; Organoids - immunology ; Paneth Cells - cytology ; Phosphorylation ; Physiological aspects ; Regeneration ; Regeneration (Biology) ; Rodents ; Science ; Signal Transduction ; Small intestine ; STAT3 Transcription Factor - metabolism ; Stem Cell Niche ; Stem cells ; Stem Cells - cytology ; Stem Cells - metabolism ; Transplants & implants</subject><ispartof>Nature (London), 2015-12, Vol.528 (7583), p.560-564</ispartof><rights>Springer Nature Limited 2015</rights><rights>COPYRIGHT 2015 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Dec 24-Dec 31, 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c608t-f92eadfefcec105736ae26f514f0fd93026a59a4bdb2bc4502fc2bb199fb6dbf3</citedby><cites>FETCH-LOGICAL-c608t-f92eadfefcec105736ae26f514f0fd93026a59a4bdb2bc4502fc2bb199fb6dbf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nature16460$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nature16460$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26649819$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lindemans, Caroline A.</creatorcontrib><creatorcontrib>Calafiore, Marco</creatorcontrib><creatorcontrib>Mertelsmann, Anna M.</creatorcontrib><creatorcontrib>O’Connor, Margaret H.</creatorcontrib><creatorcontrib>Dudakov, Jarrod A.</creatorcontrib><creatorcontrib>Jenq, Robert R.</creatorcontrib><creatorcontrib>Velardi, Enrico</creatorcontrib><creatorcontrib>Young, Lauren F.</creatorcontrib><creatorcontrib>Smith, Odette M.</creatorcontrib><creatorcontrib>Lawrence, Gillian</creatorcontrib><creatorcontrib>Ivanov, Juliet A.</creatorcontrib><creatorcontrib>Fu, Ya-Yuan</creatorcontrib><creatorcontrib>Takashima, Shuichiro</creatorcontrib><creatorcontrib>Hua, Guoqiang</creatorcontrib><creatorcontrib>Martin, Maria L.</creatorcontrib><creatorcontrib>O’Rourke, Kevin P.</creatorcontrib><creatorcontrib>Lo, Yuan-Hung</creatorcontrib><creatorcontrib>Mokry, Michal</creatorcontrib><creatorcontrib>Romera-Hernandez, Monica</creatorcontrib><creatorcontrib>Cupedo, Tom</creatorcontrib><creatorcontrib>Dow, Lukas E.</creatorcontrib><creatorcontrib>Nieuwenhuis, Edward E.</creatorcontrib><creatorcontrib>Shroyer, Noah F.</creatorcontrib><creatorcontrib>Liu, Chen</creatorcontrib><creatorcontrib>Kolesnick, Richard</creatorcontrib><creatorcontrib>van den Brink, Marcel R. M.</creatorcontrib><creatorcontrib>Hanash, Alan M.</creatorcontrib><title>Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Innate lymphoid cells increase the growth of mouse intestinal organoids via IL-22 production; recombinant IL-22 promotes growth of both mouse and human organoids, and promotes mouse intestinal stem cell (ISC) expansion and ISC-driven organoid growth via a STAT3-dependent pathway and independently of Paneth cells; IL-22 treatment in vivo enhances the recovery of ISCs from intestinal injury.
Intestinal repair mechanisms
The cellular signals supporting normal epithelial intestine maintenance through regulation of intestinal stem cell (ISC) activity are well characterized, but the signals involved in the regulation of the ISC compartment after damage are still unclear. Alan Hanash and colleagues have found that innate lymphoid cells produce interleukin-22 (IL-22) after injury to increase the growth of mouse intestinal organoids. They further show that recombinant IL-22 promotes ISC expansion in both human and mouse organoids, via a STAT3-dependent pathway and independently of the Paneth cells, which provide for ISC maintenance signals. IL-22 treatment also enhanced the recovery of ISCs from intestinal injury.
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
1
,
2
. 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
3
,
4
, 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.</description><subject>631/250/127/1213</subject><subject>631/250/1904</subject><subject>631/250/347</subject><subject>631/532/2437</subject><subject>Animals</subject><subject>Bone marrow</subject><subject>Cell cycle</subject><subject>Cytokines</subject><subject>Epidermal growth factor</subject><subject>Epithelial cells</subject><subject>Epithelial Cells - cytology</subject><subject>Epithelial Cells - immunology</subject><subject>Epithelial Cells - pathology</subject><subject>Female</subject><subject>Gene expression</subject><subject>Graft vs Host Disease - pathology</subject><subject>Health aspects</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Immune system</subject><subject>Immunity, Mucosal</subject><subject>Interleukin-22</subject><subject>Interleukins</subject><subject>Interleukins - deficiency</subject><subject>Interleukins - immunology</subject><subject>Intestinal Mucosa - cytology</subject><subject>Intestinal Mucosa - immunology</subject><subject>Intestinal Mucosa - pathology</subject><subject>Intestine, Small - cytology</subject><subject>Intestine, Small - immunology</subject><subject>Intestine, Small - pathology</subject><subject>Large intestine</subject><subject>letter</subject><subject>Mice</subject><subject>multidisciplinary</subject><subject>Organoids - cytology</subject><subject>Organoids - growth & development</subject><subject>Organoids - immunology</subject><subject>Paneth Cells - cytology</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Regeneration</subject><subject>Regeneration (Biology)</subject><subject>Rodents</subject><subject>Science</subject><subject>Signal Transduction</subject><subject>Small intestine</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Stem Cell Niche</subject><subject>Stem cells</subject><subject>Stem Cells - cytology</subject><subject>Stem Cells - metabolism</subject><subject>Transplants & implants</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp10s9rFDEUB_BBFLtWT95l0Yuio_k1mclFWBZ_LFQFrXgMmczLNnUmmSaZUv97s7aWWVlPgeTDN3kvrygeY_QaI9q8cSpNATBnHN0pFpjVvGS8qe8WC4RIU6KG8qPiQYznCKEK1-x-cUQ4Z6LBYlF82rgEoYfpp3UlIcsx-MEniEub92OyTvVlTDCUGvq-HKCzKkG3hNGmM-it6pcBtuAgqGS9e1jcM6qP8OhmPS6-v393uv5Ynnz5sFmvTkrNUZNKIwiozoDRoDGqasoVEG4qzAwynaCIcFUJxdquJa1mFSJGk7bFQpiWd62hx8Xb69xxavObNLgUVC_HYAcVfkmvrNw_cfZMbv2lZDVBjNY54PlNQPAXUy5UDjbuSlQO_BQlrissGkExzfTZP_TcTyH35Y8iWBDCZmqrepDWGZ_v1btQuWK0ERWiiGf19IDSo72Qc_RiD2mfv-IqbdUUo9x8-7of-PL_dnX6Y_35oNbBxxjA3HYMI7mbJTmbpayfzJt8a_8OTwavrkHMR24LYdaZA3m_AY_v004</recordid><startdate>20151224</startdate><enddate>20151224</enddate><creator>Lindemans, Caroline A.</creator><creator>Calafiore, Marco</creator><creator>Mertelsmann, Anna M.</creator><creator>O’Connor, Margaret H.</creator><creator>Dudakov, Jarrod A.</creator><creator>Jenq, Robert R.</creator><creator>Velardi, Enrico</creator><creator>Young, Lauren F.</creator><creator>Smith, Odette M.</creator><creator>Lawrence, Gillian</creator><creator>Ivanov, Juliet A.</creator><creator>Fu, Ya-Yuan</creator><creator>Takashima, Shuichiro</creator><creator>Hua, Guoqiang</creator><creator>Martin, Maria L.</creator><creator>O’Rourke, Kevin P.</creator><creator>Lo, Yuan-Hung</creator><creator>Mokry, Michal</creator><creator>Romera-Hernandez, Monica</creator><creator>Cupedo, Tom</creator><creator>Dow, Lukas E.</creator><creator>Nieuwenhuis, Edward E.</creator><creator>Shroyer, Noah F.</creator><creator>Liu, Chen</creator><creator>Kolesnick, Richard</creator><creator>van den Brink, Marcel R. M.</creator><creator>Hanash, Alan M.</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>ATWCN</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7ST</scope><scope>7T5</scope><scope>7TG</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88G</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>BKSAR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PCBAR</scope><scope>PDBOC</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PSYQQ</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>Q9U</scope><scope>R05</scope><scope>RC3</scope><scope>S0X</scope><scope>SOI</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20151224</creationdate><title>Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration</title><author>Lindemans, Caroline A. ; Calafiore, Marco ; Mertelsmann, Anna M. ; O’Connor, Margaret H. ; Dudakov, Jarrod A. ; Jenq, Robert R. ; Velardi, Enrico ; Young, Lauren F. ; Smith, Odette M. ; Lawrence, Gillian ; Ivanov, Juliet A. ; Fu, Ya-Yuan ; Takashima, Shuichiro ; Hua, Guoqiang ; Martin, Maria L. ; O’Rourke, Kevin P. ; Lo, Yuan-Hung ; Mokry, Michal ; Romera-Hernandez, Monica ; Cupedo, Tom ; Dow, Lukas E. ; Nieuwenhuis, Edward E. ; Shroyer, Noah F. ; Liu, Chen ; Kolesnick, Richard ; van den Brink, Marcel R. M. ; Hanash, Alan M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c608t-f92eadfefcec105736ae26f514f0fd93026a59a4bdb2bc4502fc2bb199fb6dbf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>631/250/127/1213</topic><topic>631/250/1904</topic><topic>631/250/347</topic><topic>631/532/2437</topic><topic>Animals</topic><topic>Bone marrow</topic><topic>Cell cycle</topic><topic>Cytokines</topic><topic>Epidermal growth factor</topic><topic>Epithelial cells</topic><topic>Epithelial Cells - cytology</topic><topic>Epithelial Cells - immunology</topic><topic>Epithelial Cells - pathology</topic><topic>Female</topic><topic>Gene expression</topic><topic>Graft vs Host Disease - pathology</topic><topic>Health aspects</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Immune system</topic><topic>Immunity, Mucosal</topic><topic>Interleukin-22</topic><topic>Interleukins</topic><topic>Interleukins - deficiency</topic><topic>Interleukins - immunology</topic><topic>Intestinal Mucosa - cytology</topic><topic>Intestinal Mucosa - immunology</topic><topic>Intestinal Mucosa - pathology</topic><topic>Intestine, Small - cytology</topic><topic>Intestine, Small - immunology</topic><topic>Intestine, Small - pathology</topic><topic>Large intestine</topic><topic>letter</topic><topic>Mice</topic><topic>multidisciplinary</topic><topic>Organoids - cytology</topic><topic>Organoids - growth & development</topic><topic>Organoids - immunology</topic><topic>Paneth Cells - cytology</topic><topic>Phosphorylation</topic><topic>Physiological aspects</topic><topic>Regeneration</topic><topic>Regeneration (Biology)</topic><topic>Rodents</topic><topic>Science</topic><topic>Signal Transduction</topic><topic>Small intestine</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Stem Cell Niche</topic><topic>Stem cells</topic><topic>Stem Cells - cytology</topic><topic>Stem Cells - metabolism</topic><topic>Transplants & implants</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lindemans, Caroline A.</creatorcontrib><creatorcontrib>Calafiore, Marco</creatorcontrib><creatorcontrib>Mertelsmann, Anna M.</creatorcontrib><creatorcontrib>O’Connor, Margaret H.</creatorcontrib><creatorcontrib>Dudakov, Jarrod A.</creatorcontrib><creatorcontrib>Jenq, Robert R.</creatorcontrib><creatorcontrib>Velardi, Enrico</creatorcontrib><creatorcontrib>Young, Lauren F.</creatorcontrib><creatorcontrib>Smith, Odette M.</creatorcontrib><creatorcontrib>Lawrence, Gillian</creatorcontrib><creatorcontrib>Ivanov, Juliet A.</creatorcontrib><creatorcontrib>Fu, Ya-Yuan</creatorcontrib><creatorcontrib>Takashima, Shuichiro</creatorcontrib><creatorcontrib>Hua, Guoqiang</creatorcontrib><creatorcontrib>Martin, Maria L.</creatorcontrib><creatorcontrib>O’Rourke, Kevin P.</creatorcontrib><creatorcontrib>Lo, Yuan-Hung</creatorcontrib><creatorcontrib>Mokry, Michal</creatorcontrib><creatorcontrib>Romera-Hernandez, Monica</creatorcontrib><creatorcontrib>Cupedo, Tom</creatorcontrib><creatorcontrib>Dow, Lukas E.</creatorcontrib><creatorcontrib>Nieuwenhuis, Edward E.</creatorcontrib><creatorcontrib>Shroyer, Noah F.</creatorcontrib><creatorcontrib>Liu, Chen</creatorcontrib><creatorcontrib>Kolesnick, Richard</creatorcontrib><creatorcontrib>van den Brink, Marcel R. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lindemans, Caroline A.</au><au>Calafiore, Marco</au><au>Mertelsmann, Anna M.</au><au>O’Connor, Margaret H.</au><au>Dudakov, Jarrod A.</au><au>Jenq, Robert R.</au><au>Velardi, Enrico</au><au>Young, Lauren F.</au><au>Smith, Odette M.</au><au>Lawrence, Gillian</au><au>Ivanov, Juliet A.</au><au>Fu, Ya-Yuan</au><au>Takashima, Shuichiro</au><au>Hua, Guoqiang</au><au>Martin, Maria L.</au><au>O’Rourke, Kevin P.</au><au>Lo, Yuan-Hung</au><au>Mokry, Michal</au><au>Romera-Hernandez, Monica</au><au>Cupedo, Tom</au><au>Dow, Lukas E.</au><au>Nieuwenhuis, Edward E.</au><au>Shroyer, Noah F.</au><au>Liu, Chen</au><au>Kolesnick, Richard</au><au>van den Brink, Marcel R. M.</au><au>Hanash, Alan M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2015-12-24</date><risdate>2015</risdate><volume>528</volume><issue>7583</issue><spage>560</spage><epage>564</epage><pages>560-564</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><coden>NATUAS</coden><abstract>Innate lymphoid cells increase the growth of mouse intestinal organoids via IL-22 production; recombinant IL-22 promotes growth of both mouse and human organoids, and promotes mouse intestinal stem cell (ISC) expansion and ISC-driven organoid growth via a STAT3-dependent pathway and independently of Paneth cells; IL-22 treatment in vivo enhances the recovery of ISCs from intestinal injury.
Intestinal repair mechanisms
The cellular signals supporting normal epithelial intestine maintenance through regulation of intestinal stem cell (ISC) activity are well characterized, but the signals involved in the regulation of the ISC compartment after damage are still unclear. Alan Hanash and colleagues have found that innate lymphoid cells produce interleukin-22 (IL-22) after injury to increase the growth of mouse intestinal organoids. They further show that recombinant IL-22 promotes ISC expansion in both human and mouse organoids, via a STAT3-dependent pathway and independently of the Paneth cells, which provide for ISC maintenance signals. IL-22 treatment also enhanced the recovery of ISCs from intestinal injury.
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
1
,
2
. 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
3
,
4
, 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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>26649819</pmid><doi>10.1038/nature16460</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2015-12, Vol.528 (7583), p.560-564 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4720437 |
| source | MEDLINE; SpringerLink Journals; Nature Journals Online |
| subjects | 631/250/127/1213 631/250/1904 631/250/347 631/532/2437 Animals Bone marrow Cell cycle Cytokines Epidermal growth factor Epithelial cells Epithelial Cells - cytology Epithelial Cells - immunology Epithelial Cells - pathology Female Gene expression Graft vs Host Disease - pathology Health aspects Humanities and Social Sciences Humans Immune system Immunity, Mucosal Interleukin-22 Interleukins Interleukins - deficiency Interleukins - immunology Intestinal Mucosa - cytology Intestinal Mucosa - immunology Intestinal Mucosa - pathology Intestine, Small - cytology Intestine, Small - immunology Intestine, Small - pathology Large intestine letter Mice multidisciplinary Organoids - cytology Organoids - growth & development Organoids - immunology Paneth Cells - cytology Phosphorylation Physiological aspects Regeneration Regeneration (Biology) Rodents Science Signal Transduction Small intestine STAT3 Transcription Factor - metabolism Stem Cell Niche Stem cells Stem Cells - cytology Stem Cells - metabolism Transplants & implants |
| title | Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-15T02%3A21%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Interleukin-22%20promotes%20intestinal-stem-cell-mediated%20epithelial%20regeneration&rft.jtitle=Nature%20(London)&rft.au=Lindemans,%20Caroline%20A.&rft.date=2015-12-24&rft.volume=528&rft.issue=7583&rft.spage=560&rft.epage=564&rft.pages=560-564&rft.issn=0028-0836&rft.eissn=1476-4687&rft.coden=NATUAS&rft_id=info:doi/10.1038/nature16460&rft_dat=%3Cgale_pubme%3EA438950306%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1752192243&rft_id=info:pmid/26649819&rft_galeid=A438950306&rfr_iscdi=true |