Differential role of gp130-dependent STAT and Ras signalling for haematopoiesis following bone-marrow transplantation
Bone marrow transplantation (BMT) is a complex process regulated by different cytokines and growth factors. The pleiotropic cytokine IL-6 (Interleukin-6) and related cytokines of the same family acting on the common signal transducer gp130 are known to play a key role in bone marrow (BM) engraftment...
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| Veröffentlicht in: | PloS one 2012-06, Vol.7 (6), p.e39728-e39728 |
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| description | Bone marrow transplantation (BMT) is a complex process regulated by different cytokines and growth factors. The pleiotropic cytokine IL-6 (Interleukin-6) and related cytokines of the same family acting on the common signal transducer gp130 are known to play a key role in bone marrow (BM) engraftment. In contrast, the exact signalling events that control IL-6/gp130-driven haematopoietic stem cell development during BMT remain unresolved.
Conditional gp130 knockout and knockin mice were used to delete gp130 expression (gp130(ΔMx)), or to selectively disrupt gp130-dependent Ras (gp130(ΔMxRas)) or STAT signalling (gp130(ΔMxSTAT)) in BM cells. BM derived from the respective strains was transplanted into irradiated wildtype hosts and repopulation of various haematopoietic lineages was monitored by flow cytometry.
BM derived from gp130 deficient donor mice (gp130(ΔMx)) displayed a delayed engraftment, as evidenced by reduced total white blood cells (WBC), marked thrombocytopenia and anaemia in the early phase after BMT. Lineage analysis unravelled a restricted development of CD4(+) and CD8(+) T-cells, CD19(+) B-cells and CD11b(+) myeloid cells after transplantation of gp130-deficient BM grafts. To further delineate the two major gp130-induced signalling cascades, Ras-MAPK and STAT1/3-signalling respectively, we used gp130(ΔMxRas) and gp130(ΔMxSTAT) donor BM. BMT of gp130(ΔMxSTAT) cells significantly impaired engraftment of CD4(+), CD8(+), CD19(+) and CD11b(+) cells, whereas gp130(ΔMxRas) BM displayed a selective impairment in early thrombopoiesis. Importantly, gp130-STAT1/3 signalling deficiency in BM grafts severely impaired survival of transplanted mice, thus demonstrating a pivotal role for this pathway in BM graft survival and function.
Our data unravel a vital function of IL-6/gp130-STAT1/3 signals for BM engraftment and haematopoiesis, as well as for host survival after transplantation. STAT1/3 and ras-dependent pathways thereby exert distinct functions on individual bone-marrow-lineages. |
| doi_str_mv | 10.1371/journal.pone.0039728 |
| format | Article |
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Conditional gp130 knockout and knockin mice were used to delete gp130 expression (gp130(ΔMx)), or to selectively disrupt gp130-dependent Ras (gp130(ΔMxRas)) or STAT signalling (gp130(ΔMxSTAT)) in BM cells. BM derived from the respective strains was transplanted into irradiated wildtype hosts and repopulation of various haematopoietic lineages was monitored by flow cytometry.
BM derived from gp130 deficient donor mice (gp130(ΔMx)) displayed a delayed engraftment, as evidenced by reduced total white blood cells (WBC), marked thrombocytopenia and anaemia in the early phase after BMT. Lineage analysis unravelled a restricted development of CD4(+) and CD8(+) T-cells, CD19(+) B-cells and CD11b(+) myeloid cells after transplantation of gp130-deficient BM grafts. To further delineate the two major gp130-induced signalling cascades, Ras-MAPK and STAT1/3-signalling respectively, we used gp130(ΔMxRas) and gp130(ΔMxSTAT) donor BM. BMT of gp130(ΔMxSTAT) cells significantly impaired engraftment of CD4(+), CD8(+), CD19(+) and CD11b(+) cells, whereas gp130(ΔMxRas) BM displayed a selective impairment in early thrombopoiesis. Importantly, gp130-STAT1/3 signalling deficiency in BM grafts severely impaired survival of transplanted mice, thus demonstrating a pivotal role for this pathway in BM graft survival and function.
Our data unravel a vital function of IL-6/gp130-STAT1/3 signals for BM engraftment and haematopoiesis, as well as for host survival after transplantation. STAT1/3 and ras-dependent pathways thereby exert distinct functions on individual bone-marrow-lineages.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0039728</identifier><identifier>PMID: 22745821</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Anemia ; Animals ; Biology ; Blood cells ; Bone marrow ; Bone Marrow Transplantation ; Cascades ; CD11b antigen ; CD19 antigen ; CD4 antigen ; CD8 antigen ; Cytokine Receptor gp130 - genetics ; Cytokine Receptor gp130 - metabolism ; Cytokines ; Cytometry ; Dendritic cells ; Flow cytometry ; Glycoprotein gp130 ; Grafting ; Grafts ; Growth factors ; Hematopoiesis - genetics ; Hematopoiesis - physiology ; Hematopoietic stem cell transplantation ; Hematopoietic stem cells ; Humans ; Interleukin 6 ; Interleukins ; Laboratory animals ; Leukocytes ; Ligands ; Lymphocytes B ; Lymphocytes T ; MAP kinase ; Medical research ; Medicine ; Mice ; Mice, Knockout ; Mice, Mutant Strains ; Mutation ; Myeloid cells ; ras Proteins - genetics ; ras Proteins - metabolism ; Repopulation ; Rodents ; Signal transduction ; Signal Transduction - genetics ; Signal Transduction - physiology ; Signaling ; STAT Transcription Factors - genetics ; STAT Transcription Factors - metabolism ; Stat1 protein ; STAT1 Transcription Factor - genetics ; STAT1 Transcription Factor - metabolism ; STAT3 Transcription Factor - genetics ; STAT3 Transcription Factor - metabolism ; Stem cell transplantation ; Stem cells ; Survival ; T cells ; Thrombocytopenia ; Thrombopoiesis ; Transcription factors ; Transplantation ; Tumors ; White blood cell count</subject><ispartof>PloS one, 2012-06, Vol.7 (6), p.e39728-e39728</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Kroy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Kroy et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-9797b8ad9cdc0556805ae716fd81d3de43527152331a65ca4c21624f9b0f197b3</citedby><cites>FETCH-LOGICAL-c692t-9797b8ad9cdc0556805ae716fd81d3de43527152331a65ca4c21624f9b0f197b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382143/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382143/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53770,53772,79347,79348</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22745821$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Abdelhay, Eliana Saul Furquim Werneck</contributor><creatorcontrib>Kroy, Daniela C</creatorcontrib><creatorcontrib>Hebing, Lisa</creatorcontrib><creatorcontrib>Sander, Leif E</creatorcontrib><creatorcontrib>Gassler, Nikolaus</creatorcontrib><creatorcontrib>Erschfeld, Stephanie</creatorcontrib><creatorcontrib>Sackett, Sara</creatorcontrib><creatorcontrib>Galm, Oliver</creatorcontrib><creatorcontrib>Trautwein, Christian</creatorcontrib><creatorcontrib>Streetz, Konrad L</creatorcontrib><title>Differential role of gp130-dependent STAT and Ras signalling for haematopoiesis following bone-marrow transplantation</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Bone marrow transplantation (BMT) is a complex process regulated by different cytokines and growth factors. The pleiotropic cytokine IL-6 (Interleukin-6) and related cytokines of the same family acting on the common signal transducer gp130 are known to play a key role in bone marrow (BM) engraftment. In contrast, the exact signalling events that control IL-6/gp130-driven haematopoietic stem cell development during BMT remain unresolved.
Conditional gp130 knockout and knockin mice were used to delete gp130 expression (gp130(ΔMx)), or to selectively disrupt gp130-dependent Ras (gp130(ΔMxRas)) or STAT signalling (gp130(ΔMxSTAT)) in BM cells. BM derived from the respective strains was transplanted into irradiated wildtype hosts and repopulation of various haematopoietic lineages was monitored by flow cytometry.
BM derived from gp130 deficient donor mice (gp130(ΔMx)) displayed a delayed engraftment, as evidenced by reduced total white blood cells (WBC), marked thrombocytopenia and anaemia in the early phase after BMT. Lineage analysis unravelled a restricted development of CD4(+) and CD8(+) T-cells, CD19(+) B-cells and CD11b(+) myeloid cells after transplantation of gp130-deficient BM grafts. To further delineate the two major gp130-induced signalling cascades, Ras-MAPK and STAT1/3-signalling respectively, we used gp130(ΔMxRas) and gp130(ΔMxSTAT) donor BM. BMT of gp130(ΔMxSTAT) cells significantly impaired engraftment of CD4(+), CD8(+), CD19(+) and CD11b(+) cells, whereas gp130(ΔMxRas) BM displayed a selective impairment in early thrombopoiesis. Importantly, gp130-STAT1/3 signalling deficiency in BM grafts severely impaired survival of transplanted mice, thus demonstrating a pivotal role for this pathway in BM graft survival and function.
Our data unravel a vital function of IL-6/gp130-STAT1/3 signals for BM engraftment and haematopoiesis, as well as for host survival after transplantation. STAT1/3 and ras-dependent pathways thereby exert distinct functions on individual bone-marrow-lineages.</description><subject>Analysis</subject><subject>Anemia</subject><subject>Animals</subject><subject>Biology</subject><subject>Blood cells</subject><subject>Bone marrow</subject><subject>Bone Marrow Transplantation</subject><subject>Cascades</subject><subject>CD11b antigen</subject><subject>CD19 antigen</subject><subject>CD4 antigen</subject><subject>CD8 antigen</subject><subject>Cytokine Receptor gp130 - genetics</subject><subject>Cytokine Receptor gp130 - metabolism</subject><subject>Cytokines</subject><subject>Cytometry</subject><subject>Dendritic cells</subject><subject>Flow cytometry</subject><subject>Glycoprotein gp130</subject><subject>Grafting</subject><subject>Grafts</subject><subject>Growth factors</subject><subject>Hematopoiesis - genetics</subject><subject>Hematopoiesis - physiology</subject><subject>Hematopoietic stem cell transplantation</subject><subject>Hematopoietic stem cells</subject><subject>Humans</subject><subject>Interleukin 6</subject><subject>Interleukins</subject><subject>Laboratory animals</subject><subject>Leukocytes</subject><subject>Ligands</subject><subject>Lymphocytes B</subject><subject>Lymphocytes T</subject><subject>MAP kinase</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mice, Mutant Strains</subject><subject>Mutation</subject><subject>Myeloid cells</subject><subject>ras Proteins - genetics</subject><subject>ras Proteins - metabolism</subject><subject>Repopulation</subject><subject>Rodents</subject><subject>Signal transduction</subject><subject>Signal Transduction - genetics</subject><subject>Signal Transduction - physiology</subject><subject>Signaling</subject><subject>STAT Transcription Factors - genetics</subject><subject>STAT Transcription Factors - metabolism</subject><subject>Stat1 protein</subject><subject>STAT1 Transcription Factor - genetics</subject><subject>STAT1 Transcription Factor - metabolism</subject><subject>STAT3 Transcription Factor - genetics</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Survival</subject><subject>T cells</subject><subject>Thrombocytopenia</subject><subject>Thrombopoiesis</subject><subject>Transcription factors</subject><subject>Transplantation</subject><subject>Tumors</subject><subject>White blood cell 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role of gp130-dependent STAT and Ras signalling for haematopoiesis following bone-marrow transplantation</title><author>Kroy, Daniela C ; Hebing, Lisa ; Sander, Leif E ; Gassler, Nikolaus ; Erschfeld, Stephanie ; Sackett, Sara ; Galm, Oliver ; Trautwein, Christian ; Streetz, Konrad L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-9797b8ad9cdc0556805ae716fd81d3de43527152331a65ca4c21624f9b0f197b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Analysis</topic><topic>Anemia</topic><topic>Animals</topic><topic>Biology</topic><topic>Blood cells</topic><topic>Bone marrow</topic><topic>Bone Marrow Transplantation</topic><topic>Cascades</topic><topic>CD11b antigen</topic><topic>CD19 antigen</topic><topic>CD4 antigen</topic><topic>CD8 antigen</topic><topic>Cytokine Receptor gp130 - genetics</topic><topic>Cytokine Receptor gp130 - 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Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kroy, Daniela C</au><au>Hebing, Lisa</au><au>Sander, Leif E</au><au>Gassler, Nikolaus</au><au>Erschfeld, Stephanie</au><au>Sackett, Sara</au><au>Galm, Oliver</au><au>Trautwein, Christian</au><au>Streetz, Konrad L</au><au>Abdelhay, Eliana Saul Furquim Werneck</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Differential role of gp130-dependent STAT and Ras signalling for haematopoiesis following bone-marrow transplantation</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-06-22</date><risdate>2012</risdate><volume>7</volume><issue>6</issue><spage>e39728</spage><epage>e39728</epage><pages>e39728-e39728</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Bone marrow transplantation (BMT) is a complex process regulated by different cytokines and growth factors. The pleiotropic cytokine IL-6 (Interleukin-6) and related cytokines of the same family acting on the common signal transducer gp130 are known to play a key role in bone marrow (BM) engraftment. In contrast, the exact signalling events that control IL-6/gp130-driven haematopoietic stem cell development during BMT remain unresolved.
Conditional gp130 knockout and knockin mice were used to delete gp130 expression (gp130(ΔMx)), or to selectively disrupt gp130-dependent Ras (gp130(ΔMxRas)) or STAT signalling (gp130(ΔMxSTAT)) in BM cells. BM derived from the respective strains was transplanted into irradiated wildtype hosts and repopulation of various haematopoietic lineages was monitored by flow cytometry.
BM derived from gp130 deficient donor mice (gp130(ΔMx)) displayed a delayed engraftment, as evidenced by reduced total white blood cells (WBC), marked thrombocytopenia and anaemia in the early phase after BMT. Lineage analysis unravelled a restricted development of CD4(+) and CD8(+) T-cells, CD19(+) B-cells and CD11b(+) myeloid cells after transplantation of gp130-deficient BM grafts. To further delineate the two major gp130-induced signalling cascades, Ras-MAPK and STAT1/3-signalling respectively, we used gp130(ΔMxRas) and gp130(ΔMxSTAT) donor BM. BMT of gp130(ΔMxSTAT) cells significantly impaired engraftment of CD4(+), CD8(+), CD19(+) and CD11b(+) cells, whereas gp130(ΔMxRas) BM displayed a selective impairment in early thrombopoiesis. Importantly, gp130-STAT1/3 signalling deficiency in BM grafts severely impaired survival of transplanted mice, thus demonstrating a pivotal role for this pathway in BM graft survival and function.
Our data unravel a vital function of IL-6/gp130-STAT1/3 signals for BM engraftment and haematopoiesis, as well as for host survival after transplantation. STAT1/3 and ras-dependent pathways thereby exert distinct functions on individual bone-marrow-lineages.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22745821</pmid><doi>10.1371/journal.pone.0039728</doi><tpages>e39728</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-06, Vol.7 (6), p.e39728-e39728 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1325027270 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Analysis Anemia Animals Biology Blood cells Bone marrow Bone Marrow Transplantation Cascades CD11b antigen CD19 antigen CD4 antigen CD8 antigen Cytokine Receptor gp130 - genetics Cytokine Receptor gp130 - metabolism Cytokines Cytometry Dendritic cells Flow cytometry Glycoprotein gp130 Grafting Grafts Growth factors Hematopoiesis - genetics Hematopoiesis - physiology Hematopoietic stem cell transplantation Hematopoietic stem cells Humans Interleukin 6 Interleukins Laboratory animals Leukocytes Ligands Lymphocytes B Lymphocytes T MAP kinase Medical research Medicine Mice Mice, Knockout Mice, Mutant Strains Mutation Myeloid cells ras Proteins - genetics ras Proteins - metabolism Repopulation Rodents Signal transduction Signal Transduction - genetics Signal Transduction - physiology Signaling STAT Transcription Factors - genetics STAT Transcription Factors - metabolism Stat1 protein STAT1 Transcription Factor - genetics STAT1 Transcription Factor - metabolism STAT3 Transcription Factor - genetics STAT3 Transcription Factor - metabolism Stem cell transplantation Stem cells Survival T cells Thrombocytopenia Thrombopoiesis Transcription factors Transplantation Tumors White blood cell count |
| title | Differential role of gp130-dependent STAT and Ras signalling for haematopoiesis following bone-marrow transplantation |
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