Clinical significance and therapeutic value of glutathione peroxidase 3 (GPx3) in hepatocellular carcinoma

AIMS: We aimed to investigate the clinical significance of GPx3 in hepatocellular carcinoma (HCC) and to characterize its tumor suppressive role. METHODS: HCC patients (113) who underwent hepatectomy were recruited to examine the clinical relevance of GPx3. The tumor suppressive role of GPx3 was studied by administration of recombinant GPx3 (rGPx3) or over-expression of GPx3 in HCC cells in vitro and in vivo. The therapeutic value of GPx3 for HCC was further investigated using human induced pluripotent stem cell derived mesenchymal stem cells (hiPSC-MSCs) as its delivery vehicle. RESULTS: Down-regulation of GPx3 significantly correlated with advanced tumor stage (P = 0.024), venous infiltration (P = 0.043) and poor overall survival (P = 0.007) after hepatectomy. Lower plasma GPx3 in HCC patients was significantly associated with larger tumor size (P = 0.011), more tumor nodules (P = 0.032) and higher recurrence (P = 0.016). Over-expression of GPx3 or administration of rGPx3 significantly inhibited proliferation and invasiveness of HCC cells in vitro and in vivo. Tumor suppressive activity of GPx3 was mediated through Erk-NFκB-SIP1 pathway. GPx3 could be delivered by hiPSC-MSCs into the tumor and exhibited tumor suppressive activity in vivo. CONCLUSIONS: GPx3 is a tumor suppressor gene in HCC and may possess prognostic and therapeutic value for HCC patients.published_or_final_versio

Isolation and characterisation of human gingival margin-derived STRO-1/MACS+ and MACS− cell populations

Recently, gingival margin-derived stem/progenitor cells isolated via STRO-1/magnetic activated cell sorting (MACS) showed remarkable periodontal regenerative potential in vivo. As a second-stage investigation, the present study's aim was to perform in vitro characterisation and comparison of the stem/progenitor cell characteristics of sorted STRO-1-positive (MACS+) and STRO-1-negative (MACS−) cell populations from the human free gingival margin. Cells were isolated from the free gingiva using a minimally invasive technique and were magnetically sorted using anti-STRO-1 antibodies. Subsequently, the MACS+ and MACS− cell fractions were characterized by flow cytometry for expression of CD14, CD34, CD45, CD73, CD90, CD105, CD146/MUC18 and STRO-1. Colony-forming unit (CFU) and multilineage differentiation potential were assayed for both cell fractions. Mineralisation marker expression was examined using real-time polymerase chain reaction (PCR). MACS+ and MACS− cell fractions showed plastic adherence. MACS+ cells, in contrast to MACS− cells, showed all of the predefined mesenchymal stem/progenitor cell characteristics and a significantly higher number of CFUs (P<0.01). More than 95% of MACS+ cells expressed CD105, CD90 and CD73; lacked the haematopoietic markers CD45, CD34 and CD14, and expressed STRO-1 and CD146/MUC18. MACS− cells showed a different surface marker expression profile, with almost no expression of CD14 or STRO-1, and more than 95% of these cells expressed CD73, CD90 and CD146/MUC18, as well as the haematopoietic markers CD34 and CD45 and CD105. MACS+ cells could be differentiated along osteoblastic, adipocytic and chondroblastic lineages. In contrast, MACS− cells demonstrated slight osteogenic potential. Unstimulated MACS+ cells showed significantly higher expression of collagen I (P<0.05) and collagen III (P<0.01), whereas MACS− cells demonstrated higher expression of osteonectin (P<0.05; Mann–Whitney). The present study is the first to compare gingival MACS+ and MACS− cell populations demonstrating that MACS+ cells, in contrast to MACS− cells, harbour stem/progenitor cell characteristics. This study also validates the effectiveness of the STRO-1/MACS+ technique for the isolation of gingival stem/progenitor cells. Human free gingival margin-derived STRO-1/MACS+ cells are a unique renewable source of multipotent stem/progenitor cells

Advances in research of cancer stem cells

OBJECTIVE: To summarize the advances in the researches about cancer stem cells in last 5 years. METHODS: With the keywords "neoplasms, stem cell and cancer stem cells", 2 760 papers published from Jan 1979 to Dec 2008 were searched in the Pubmed databases. Adoptive standards: 1) the surface markers, drug-resistance mechanism and signal transduction pathways of cancer stem cells. 2) the origin of cancer stem cells. 3) cancer stem cells and clinical oncology. According to the adoptive standards, 33 top-quality papers were chosen for reviewing. RESULTS: Cancer stem cells have the properties of self-renewal and differentiation, with special cell surface markers and drug-resistance. The signal transduction pathways of cancer stem cells including Wnt, Notch, Hedgehog and Bmi-1 were abnormal. Cancer stem cells are the origin of malignant tumor's growth, recurrence and metastasis, having been the target of anti-cancer research. CONCLUSIONS: Rapid progress has been made in the research about cancer stem cells. The thorough study on cancer stem cells is significant for the diagnosis, treatment and prognosis evaluation of malignant tumor. The theory of cancer stem cells will change the current cancer diagnosis and treatment model.link_to_subscribed_fulltex

Induced pluripotent stem cell-derived mesenchymal stem cells exert growth differentiation factor-15-dependent paracrine effect in cigarette smoke medium-induced cardiomyocyte injury

Introduction: Mesenchymal stem cells (MSCs) are emerging as a potential cell-based therapy for cardiovascular diseases (CVDs), in which cigarette smoking is the major risk factor. Our previous findings demonstrated that the secretions from human induced pluripotent stem cell–derived mesenchymal stem cells (iPSC-MSCs) had a superior effect over bone marrow–derived MSCs (BM-MSCs) in attenuating cigarette smoke medium (CSM)–induced cardiomyocytes injury. Secretions of iPSC-MSCs contain higher level of growth differentiation factor-15 (GDF-15) than BM-MSCs,1 which has been regarded as a cardioprotective protein against cell apoptosis. The aim of this study was to investigate whether GDF-15 is responsible for the superior therapeutic effects of secretions from iPSC-MSCs. Methods: The human AC16 cardiomyocyte cell line was cultured in DMEM/F12 containing 12.5% fetal bovine serum. The CSM and conditioned medium (CdM) from iPSC-MSCs or recombinant human GDF-15 (rhGDF-15; same concentration as detected in CdM from iPSC-MSC) were added into cells and incubated for 24 hours. Cells were harvested to perform H2DCF-DA and MitoSox Red assays to determine cellular reactive oxygen species (ROS) and mitochondrial superoxide by flow cytometry. Apoptotic cells were measured with Annexin V apoptosis detection kit. JC-1 assay was conducted on cells to measure mitochondrial membrane potential. Results: CdM from iPSC-MSC had a superior effect on the inhibition of CSM-induced cell apoptosis than that from BM-MSCs, along with reduced cleaved caspase 3 and cleaved PARP. CdM from iPSC-MSCs or rhGDF-15 significantly reduced CSM-induced ROS, mitochondrial superoxide production and cell apoptosis, respectively. Recombinant hGDF-15 partially restored mitochondrial function by maintaining mitochondrial membrane potential compared to CdM from iPSC-MSCs. Conclusion: These data suggest that iPSC-MSCs-mediated protective effects on cardiomyocytes by inhibiting cell apoptosis and oxidative stress and attenuating mitochondrial dysfunction are likely to be GDF-15-dependent paracrine action in vitro. Reference 1. Zhang Y, Liang X, Liao S, et al. Potent Paracrine Effects of human induced Pluripotent Stem Cell-derived Mesenchymal Stem Cells Attenuate Doxorubicin-induced Cardiomyopathy. Sci Rep 2015;5:11235

Novel mechanism for tissue repair of human induced pluripotent stem cells derived mesenchymal stem cells during liver regeneration

Wiley free (Conference abstract)link_to_OA_fulltextFrancisco, CA, 16-19, May 2012. In Liver Transplantation, 2012, v. 18 n. 1, p. S138-S139, abstract no. O-17

Analysis of complement-bound HCV complexes using a novel immuno-capture RT-PCR method

Recently, more and more evidence has supported the hypothesis that liver cell injury was immune-mediated in patients with hepatitis C virus (HCV) infection, and that circulating immune complexes (CICs) might play a role in the pathogenesis of chronic hepatitis C (HQ. In the present study, we have combined immuno-capture and reverse transcriptase-polymerase chain reaction (RT-PCR), and developed a quick method of high specificity for the detection of complement-bound HCV-CIC. We found that there were higher frequencies of HCV-C1q CIC than that of HCV-factor B, and there was a deviation of complement from immunoglobulin (Ig) in HCV-CIC. These findings suggest that immuno-capture RT-PCR (iRT-PCR) for the detection of HCV-bound CIC is a valuable method for the analysis of the composition of the immune complexes, and for the understanding of host immune response and immune pathogenesis in HCV-infected individuals

Analysis of complement-bound hepatitis B virus complexes by an immuno-capture polymerase chain reaction method

Hepatitis B Virus (HBV) can be present in the circulating blood either as a free virus or as a virion-immunoglobulin (Ig) complex with or without complement. However, information regarding the complement-bound HBV circulating immune complexes (CIC) in HBV-infected patients is currently not available. In the present study, we have combined immuno-capture and polymerase chain reaction (PCR) and developed a quick method of high specificity for the detection of complement-bound HBV CIC. We found that the frequency of HBV-factor B was associated with clinical types of hepatitis B (HB) but not with that of HBV-C1q. Moreover, increased frequency at P < 0.05 were found for HBV/C1q-CIC in the group with normal total bilirubin (TBIL) and for HBV/factor B-CIC in the group with positive hepatitis B e antigen (HBeAg). These findings suggest that the immuno-capture PCR (iPCR) for the detection of HBV-bound CIC is a valuable method for analysis of the composition of the immune complexes and for the understanding of host immune response and immune pathogenesis in HBV-infected individuals. In summary, iPCR is a valuable method for analysis of the composition of the immune complexes, which may provide new and valuable insights into HBV pathogenesis