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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.
Liver Transpl 2010; 16(10):1195-206LT

Abstract

Adult 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 × 10(6) 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, α-fetoprotein, CCAAT-enhancer binding protein α, α-1-antitryspin, and hepatocyte nuclear factor-3β. Immunofluorescent staining revealed that these cells were positive for albumin, α-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 β-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 β-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.

Authors+Show Affiliations

Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20879018

Citation

Lam, Shuk Pik, et al. "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." Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, vol. 16, no. 10, 2010, pp. 1195-206.
Lam SP, Luk JM, Man K, et al. 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. Liver Transpl. 2010;16(10):1195-206.
Lam, S. P., Luk, J. M., Man, K., Ng, K. T., Cheung, C. K., Rose-John, S., & Lo, C. M. (2010). 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. Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 16(10), pp. 1195-206. doi:10.1002/lt.22136.
Lam SP, et al. 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. Liver Transpl. 2010;16(10):1195-206. PubMed PMID: 20879018.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Lam,Shuk Pik, AU - Luk,John M, AU - Man,Kwan, AU - Ng,Kevin T P, AU - Cheung,Cindy K, AU - Rose-John,Stefan, AU - Lo,Chung Mau, PY - 2010/9/30/entrez PY - 2010/9/30/pubmed PY - 2011/1/14/medline SP - 1195 EP - 206 JF - Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society JO - Liver Transpl. VL - 16 IS - 10 N2 - Adult 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 × 10(6) 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, α-fetoprotein, CCAAT-enhancer binding protein α, α-1-antitryspin, and hepatocyte nuclear factor-3β. Immunofluorescent staining revealed that these cells were positive for albumin, α-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 β-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 β-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. SN - 1527-6473 UR - https://www.unboundmedicine.com/medline/citation/20879018/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_ L2 - https://doi.org/10.1002/lt.22136 DB - PRIME DP - Unbound Medicine ER -