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.

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-3ß. 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 ß-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 ß-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.

Cardiotrophin-1 enhances regeneration of cirrhotic liver remnant after hepatectomy through promotion of angiogenesis and cell proliferation.

BACKGROUND/AIM: Hepatic resection is not applicable to a certain proportion of hepatocellular carcinoma patients owing to an insufficient liver function reserve. The present study was designed to investigate the effects of cardiotrophin-1 (CT-1) on improving the function of CCl(4)-induced cirrhotic liver remnant after major hepatectomy. METHODS: CT-1 was administered to rats after hepatectomy according to different protocols. RESULTS: A double-dose CT-1 protocol improved liver function, enlarged the volume of liver remnant, upregulated the expression of von Willebrand factor and increased the number of BrdU(+) or Ki-67(+) hepatocytes. Administration of CT-1 enhanced the expression of nuclear factor-kappaB (P65), vascular endothelial growth factor (VEGF), CyclinD1 and p42/44 in the liver remnant. However, the effects of CT-1 were blocked by a VEGF receptor blocker, PTK787. Although the expression of gp130, a receptor of CT-1, was downregulated in the diseased hepatocytes isolated from the cirrhotic liver, CT-1 could still stimulate the cell proliferation. CT-1 administration enhanced the expression of P65 and VEGF in the diseased hepatocytes, but the augmented P65 and VEGF expression was blocked by PTK787 administration. CONCLUSION: Short-term administration of CT-1 could improve the function of cirrhotic liver remnant and stimulate liver regeneration through promotion of angiogenesis and cell proliferation.

Inhibition of Stat3 activity by YC-1 enhances chemo-sensitivity in hepatocellular carcinoma.

The present study investigated the effect of YC-1, a novel anti-cancer agent, on the chemo-sensitivity of hepatocellular carcinoma (HCC). YC-1 was administered with chemo-cytotoxic drug, cisplatin, both in vitro and in vivo. YC-1 alone downregulated the expression of phosphorylated form of signal transducers and activators of transcription 3 (P-Stat3[705]), a key mediator in chemo-resistance. When combined with cisplatin, YC-1 further promoted tumor cell apoptosis, decreased the expression of P-Stat3(705), Bcl-xL, CyclinD1 and survivin, and induced the cleavage of caspase 9 and PARP. Overexpression of Stat3 reversed YC-1 induced cell death. YC-1 inhibited Stat3 activity by enhancing the polyubiquitination of P-Stat3(705) induced by cisplatin. In the in vivo setting, YC-1 combined with cisplatin remarkably suppressed tumor growth in a HCC xenograft model, and this effect was also accompanied by YC-1 mediated downregulation of P-Stat3(705), Bcl-xL, Cyclin D1 and survivin, and induction of cleaved caspase 9 and PARP in the tumor tissues. In conclusion, the present study demonstrated a novel anti-cancer effect of YC-1 in enhancing chemo-sensitivity of HCC cells to cisplatin through a Stat3 dependent manner. This finding provides insight into design of a new therapeutic strategy to improve efficacy of chemotherapy in HCC patients.