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Article: Activation of interleukin-6-induced glycoprotein 130/signal transducer and activator of transcription 3 pathway in mesenchymal stem cells enhances hepatic differentiation, proliferation, and liver regeneration

TitleActivation of interleukin-6-induced glycoprotein 130/signal transducer and activator of transcription 3 pathway in mesenchymal stem cells enhances hepatic differentiation, proliferation, and liver regeneration
Authors
Issue Date2010
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jtoc/106570021
Citation
Liver Transplantation, 2010, v. 16 n. 10, p. 1195-1206 How to Cite?
AbstractAdult bone marrow-derived mesenchymal stem cells (MSCs) exist in all living species and are capable of differentiating into different types of specific cells. In this study, we demonstrate the therapeutic effectiveness of rat MSC transplantation in D-galactosamine (GalN)-induced acute liver injury and identified the novel pathways which are involved in hepatic differentiation of MSCs. In vivo, intraportal transplantation with 5 106 MSCs at 24 hours after GalN administration resulted in significant reduction in serum levels of alanine aminotransferase, aspartate aminotransferase, and total bilirubin compared to the control group. Engrafted MSCs actively proliferated, differentiated, and further enhanced hepatocyte proliferation activity. In vitro, coculture of MSCs with GalN-induced injured hepatocytes showed efficient differentiation and was evidenced by progressive increase in messenger RNA levels of hepatic markers, including albumin, a-fetoprotein, CCAAT-enhancer binding protein a, a-1-antitryspin, and hepatocyte nuclear factor-3b. Immunofluorescent staining revealed that these cells were positive for albumin, a-fetoprotein, and cytokeratin 18, but not clusters of differentiation 34, cytokeratin 19, or OV6. During hepatic differentiation, signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling were constantly activated, and a gradual down-regulation of b-catenin expression in messenger RNA and protein levels was detected. Hyper-interleukin-6 fusion protein but not interleukin-6 (IL-6) alone caused reduction in b-catenin expression associated with the up-regulation of Wnt-5a in MSCs via activating the glycoprotein 130 (gp130)-mediated STAT3 signaling pathway, which indicates the operation of the trans-signaling mechanism. Activation of IL-6/gp130-mediated STAT3 signaling pathway in MSCs triggered wound healing, cell migration, and proliferation. In conclusion, transplantation of MSCs promotes cell proliferation and organ repair, and activation of IL-6/gp130-mediated STAT3 signaling pathway via soluble IL-6 receptor is crucial in hepatic differentiation of MSCs. © 2010 AASLD.
Persistent Identifierhttp://hdl.handle.net/10722/129395
ISSN
2015 Impact Factor: 3.951
2015 SCImago Journal Rankings: 1.763
ISI Accession Number ID
Funding AgencyGrant Number
Deutsche ForschungsgemeinschaftSFB415
TPB5
RO632/13-1
Cluster of Excellence "Inflammation at Interfaces''
Research Grants CouncilHKU5/CRF/08
Funding Information:

We thank Mr. Jensen To, Dr. Jana Woo, and Ms. Mei-Yu Hu for their excellent technical assistance. The work of Professor Stefan Rose-John was supported by grants of the Deutsche Forschungsgemeinschaft (SFB415, TPB5, and grant RO632/13-1) and by the Cluster of Excellence "Inflammation at Interfaces''. The work was also partially supported by Research Grants Council Collaborative Research Funding (HKU5/CRF/08).

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DC FieldValueLanguage
dc.contributor.authorLam, SPen_HK
dc.contributor.authorLuk, JMen_HK
dc.contributor.authorMan, Ken_HK
dc.contributor.authorNg, KTPen_HK
dc.contributor.authorCheung, CKen_HK
dc.contributor.authorStefan, RJen_HK
dc.contributor.authorLo, CMen_HK
dc.date.accessioned2010-12-23T08:36:44Z-
dc.date.available2010-12-23T08:36:44Z-
dc.date.issued2010en_HK
dc.identifier.citationLiver Transplantation, 2010, v. 16 n. 10, p. 1195-1206en_HK
dc.identifier.issn1527-6465en_HK
dc.identifier.urihttp://hdl.handle.net/10722/129395-
dc.description.abstractAdult bone marrow-derived mesenchymal stem cells (MSCs) exist in all living species and are capable of differentiating into different types of specific cells. In this study, we demonstrate the therapeutic effectiveness of rat MSC transplantation in D-galactosamine (GalN)-induced acute liver injury and identified the novel pathways which are involved in hepatic differentiation of MSCs. In vivo, intraportal transplantation with 5 106 MSCs at 24 hours after GalN administration resulted in significant reduction in serum levels of alanine aminotransferase, aspartate aminotransferase, and total bilirubin compared to the control group. Engrafted MSCs actively proliferated, differentiated, and further enhanced hepatocyte proliferation activity. In vitro, coculture of MSCs with GalN-induced injured hepatocytes showed efficient differentiation and was evidenced by progressive increase in messenger RNA levels of hepatic markers, including albumin, a-fetoprotein, CCAAT-enhancer binding protein a, a-1-antitryspin, and hepatocyte nuclear factor-3b. Immunofluorescent staining revealed that these cells were positive for albumin, a-fetoprotein, and cytokeratin 18, but not clusters of differentiation 34, cytokeratin 19, or OV6. During hepatic differentiation, signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling were constantly activated, and a gradual down-regulation of b-catenin expression in messenger RNA and protein levels was detected. Hyper-interleukin-6 fusion protein but not interleukin-6 (IL-6) alone caused reduction in b-catenin expression associated with the up-regulation of Wnt-5a in MSCs via activating the glycoprotein 130 (gp130)-mediated STAT3 signaling pathway, which indicates the operation of the trans-signaling mechanism. Activation of IL-6/gp130-mediated STAT3 signaling pathway in MSCs triggered wound healing, cell migration, and proliferation. In conclusion, transplantation of MSCs promotes cell proliferation and organ repair, and activation of IL-6/gp130-mediated STAT3 signaling pathway via soluble IL-6 receptor is crucial in hepatic differentiation of MSCs. © 2010 AASLD.en_HK
dc.languageengen_US
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jtoc/106570021en_HK
dc.relation.ispartofLiver Transplantationen_HK
dc.rightsLiver Transplantation. Copyright © John Wiley & Sons, Inc.-
dc.subject.meshCell Differentiation-
dc.subject.meshCell Proliferation-
dc.subject.meshCytokine Receptor gp130 - metabolism-
dc.subject.meshDrug-Induced Liver Injury - etiology - metabolism - pathology - surgery-
dc.subject.meshHepatocytes - metabolism - pathology - transplantation-
dc.titleActivation of interleukin-6-induced glycoprotein 130/signal transducer and activator of transcription 3 pathway in mesenchymal stem cells enhances hepatic differentiation, proliferation, and liver regenerationen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1527-6465&volume=16&issue=10&spage=1195&epage=1206&date=2010&atitle=Activation+of+interleukin-6-induced+glycoprotein+130/signal+transducer+and+activator+of+transcription+3+pathway+in+mesenchymal+stem+cells+enhances+hepatic+differentiation,+proliferation,+and+liver+regeneration-
dc.identifier.emailLuk, JM: jmluk@hkucc.hku.hken_HK
dc.identifier.emailMan, K: kwanman@hku.hken_HK
dc.identifier.emailNg, KTP: ledodes@hku.hken_HK
dc.identifier.emailLo, CM: chungmlo@hkucc.hku.hken_HK
dc.identifier.authorityLuk, JM=rp00349en_HK
dc.identifier.authorityMan, K=rp00417en_HK
dc.identifier.authorityNg, KTP=rp01720en_HK
dc.identifier.authorityLo, CM=rp00412en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/lt.22136en_HK
dc.identifier.pmid20879018-
dc.identifier.scopuseid_2-s2.0-79952118341en_HK
dc.identifier.hkuros183294en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79952118341&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume16en_HK
dc.identifier.issue10en_HK
dc.identifier.spage1195en_HK
dc.identifier.epage1206en_HK
dc.identifier.isiWOS:000283070000010-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectLiver Transplantation Research Centre: A Multidisciplinary Study for Liver Graft Injury-
dc.identifier.scopusauthoridLam, SP=24071037800en_HK
dc.identifier.scopusauthoridLuk, JM=7006777791en_HK
dc.identifier.scopusauthoridMan, K=7101754072en_HK
dc.identifier.scopusauthoridNg, KTP=7403178513en_HK
dc.identifier.scopusauthoridCheung, CK=8714367400en_HK
dc.identifier.scopusauthoridStefan, RJ=7005713466en_HK
dc.identifier.scopusauthoridLo, CM=7401771672en_HK

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