Ruiyun Xu

Differentiation of bone marrow-derived mesenchymal stem cells into hepatocyte-like cells in an alginate scaffold

Objectives:  Alginate scaffolds are the most frequently investigated biomaterials in tissue engineering. Tissue engineering techniques that generate liver tissue have become important for treatment of a number of liver diseases and recent studies indicate that bone marrow‐derived stem cells (BMSCs) can differentiate into hepatocyte‐like cells. The goal of the study described here, was to examine in vitro hepatic differentiation potential of BMSCs cultured in an alginate scaffold.

Hedgehog-mediated paracrine interaction between hepatic stellate cells and marrow-derived mesenchymal stem cells

During liver injury, bone marrow-derived mesenchymal stem cells (MSCs) can migrate and differentiate into hepatocytes. Hepatic stellate cell (SC) activation is a pivotal event in the development of liver fibrosis. Therefore, we hypothesized that SCs may play an important role in regulating MSC proliferation and differentiation through the paracrine signaling pathway. We demonstrate that MSCs and SCs both express hedgehog (Hh) pathway components, including its ligands, receptors, and target genes. Transwell co-cultures of SCs and MSCs showed that the SCs produced sonic hedgehog (Shh), which enhanced the proliferation and differentiation of MSCs. These findings demonstrate that SCs indirectly modulate the activity of MSCs in vitro via the Hh pathway, and provide a plausible explanation for the mechanisms of transplanted MSCs in the treatment of liver fibrosis.

NP603, a novel and potent inhibitor of FGFR1 tyrosine kinase, inhibits hepatic stellate cell proliferation and ameliorates hepatic fibrosis in rats

Fibroblast growth factor 2 (FGF-2) and its main receptor FGFR1 have been shown to promote hepatic stellate cell (HSC) activation and proliferation. However, scant information is available on the anti-fibrogenic activity of FGFR1 inhibitors. The aim of this study was to assess the impact of a selective FGFR1 tyrosine kinase inhibitor NP603 on HSC proliferation and hepatic fibrosis. We demonstrated that rat primary HSCs secreted significant amounts of FGF-2, and its tyrosine phosphorylation of FGFR1 was attenuated by NP603. NP603 inhibited HSC activaton by measuring the expression of α-smooth muscle actin (α-SMA) and the production of type I collagen using ELISA. Furthermore, NP603 (25 μM) in vitro strongly suppressed HSC growth induced by FGF-2 (10 ng/ml) and FCS. This effect correlated with the suppression of extracellular-regulated kinase (ERK) activity and its downstream targets cyclin D1 and p21. In addition, PO NP603 (20 mg·kg(-1)·day(-1)) administration significantly decreased hepatic collagen deposition and α-SMA expression in CCl(4)-treated rats. Collectively, these studies suggest that selective blocking of the FGFR1-mediated pathway could be a promising therapeutic approach for the treatment of hepatic fibrosis.

Hypoxia-induced secretion of platelet-derived growth factor‑BB by hepatocellular carcinoma cells increases activated hepatic stellate cell proliferation, migration and expression of vascular endothelial growth factor‑A

Angiogenesis has an important function in the proliferation and metastasis of hepatocellular carcinoma (HCC) under a hypoxic tumor microenvironment. Activated hepatic stellate cells (HSCs) infiltrate the stroma of liver tumors and potently increase angiogenesis through tumor-stromal interactions, however, the exact mechanism by which this occurs is unknown. The present study aimed to investigate the paracrine effects of HCC-derived platelet-derived growth factor-BB (PDGF-BB) on HSCs under hypoxic conditions. It was demonstrated that PDGF-BB expression was markedly increased in HepG2 cells exposed to hypoxia. Conditioned medium (CM) from HepG2 cells stimulated LX-2 cell proliferation, migration and vascular endothelial growth factor-A (VEGF-A) expression. It was then determined that blocking PDGF-BB expression in HepG2-CM abolished these effects on LX-2 cells. The ectopic expression of PDGF-BB in HepG2 cells strongly affected LX-2 cell proliferation, migration and VEGF-A expression. In conclusion, the present study suggests that hypoxia-induced PDGF-BB secretion by HCC cells stimulates HSCs to accumulate and proliferate in the tumor stroma and the enhanced VEGF-A expression in HSCs may promote HCC angiogenesis.

Activation of Notch1 signaling by marrow-derived mesenchymal stem cells through cell-cell contact inhibits proliferation of hepatic stellate cells.

AIMS Bone marrow-derived mesenchymal stem cells (BMSCs) have been reported in many studies to reduce liver fibrosis. Apart from the paracrine mechanism by which the antifibrotic effects of BMSCs inhibit activated hepatic stellate cells (HSCs), the effects of direct interplay and juxtacrine signaling between the two cell types are poorly understood. The purpose of this study was to explore the underlying mechanisms by which BMSCs modulate the function of activated HSCs. MAIN METHODS We show here that BMSCs directly cocultured with HSCs significantly suppressed the proliferation and α-smooth muscle actin (α-SMA) expression of HSCs. Moreover, the Notch1 and Hes1 mRNA levels and the Hes1 protein level in cocultured HSCs were evidently higher than in other models. Blocking the Notch signaling pathway with Notch1 siRNA caused the increased expression of phospho-Akt and greater cell growth of cocultured HSCs. This effect was attenuated by the PI3K inhibitor LY294002. KEY FINDINGS In conclusion, our results demonstrated that BMSCs remarkably inhibited the proliferation of HSCs through a cell-cell contact mode that was partially mediated by Notch pathway activation. In addition, the PI3K/Akt pathway is involved in HSC growth inhibition by the Notch pathway. SIGNIFICANCE These findings demonstrated that BMSCs directly modulate HSCs in vitro via Notch signaling cascades. Our results may provide new insights into the treatment of hepatic fibrosis with BMSCs.

Role of activated hepatic stellate cells in proliferation and metastasis of hepatocellular carcinoma

Cancer is not only influenced by specific tumor cells but also by the stromal microenvironment. Upon liver damage, activated hepatic stellate cells (aHSC) become highly proliferative myofibroblast‐like cells and are thought to secrete molecules that influence development of hepatocellular carcinoma (HCC). The aim of this study was to investigate the role of aHSC in the development of HCC.

Activated hepatic stellate cells promote angiogenesis via interleukin-8 in hepatocellular carcinoma

BackgroundChemokines have been recognized as important modulators of angiogenesis, and they play critical roles in the development and metastasis of hepatocellular carcinoma (HCC), although their origins and latent molecular mechanisms remain elusive. The aim of this study was to investigate how activated hepatic stellate cells (a-HSCs) promote angiogenesis in HCC.MethodsA total of 22 HCC patients were enrolled randomly. We used immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay (ELISA) to analyse the production of interleukin-8 (IL-8) in a-HSCs derived from HCC tissues. The angiogenic effects of IL-8 in vitro and in vivo were assessed by ELISA, real-time quantitative polymerase chain reaction, capillary tube formation assay, and chick embryo chorioallantoic membrane assay.ResultsThe present study showed that IL-8 was enriched predominantly in the tumour stroma of HCC tissues and was mainly derived from a-HSCs, rather than from hepatoma cells, in vivo and in vitro. Angiogenesis was most active at the invading edge, which was close to the a-HSCs. The angiogenic effect was dramatically attenuated by an IL-8 neutralizing antibody both in vitro and in vivo. Moreover, the IL-8 neutralizing antibody down-regulated Ser727-phosphorylated STAT3 levels in hepatoma cells treated with a-HSCs conditioned medium.ConclusionsThese findings reveal that a-HSCs within the stroma of HCC contribute to tumour angiogenesis via IL-8.

Primary gastrointestinal stromal tumors: Current advances in diagnostic biomarkers, prognostic factors and management of its duodenal location

Gastrointestinal stromal tumors (GIST) constitute 1-3% of all gastrointestinal malignancies and is the most common mesenchymal tumor of the gastrointestinal tract. Although GIST were first described in the literature in the year 1941, important advances of kit mutation and tyrosine kinase inhibitors were not made to understand and manage GIST until the last decade. Here current advances in research of possible cellular origin, diagnostic biomarkers and prognostic factors of primary GIST are reviewed, and the management of primary duodenal GIST is focused on due to its specific location. It is possible that personalized assessment and therapy will turn out to be another milestone for primary GIST.

Pseudomyxoma peritonei as an intractable disease and its preoperative assessment to help improve prognosis after surgery: A review of the literature.

Pseudomyxoma peritonei (PMP) is a rare and intractable disease with an estimated incidence of one per million population per year. Many aspects of PMP need to be fully and precisely understood; these include its preoperative assessment, i.e. diagnosis, early diagnosis, pathologic classification, and staging according to the peritoneal cancer index, and its surgical treatment. This review focuses on elements of preoperative assessment and surgery using the Sugarbaker procedure to help improve the prognosis for patients with PMP. Accurate data on the incidence of PMP must be based on large populations rather than estimates, and much work needs to be done especially in China. Special attention should be paid to its preoperative assessment. Also proposed here are steps to manage PMP with an emphasis on preoperative assessment.

Delayed bronchobiliary fistula and cholangiolithiasis following percutaneous radio frequency ablation for hepatocellular carcinoma

Although percutaneous radio frequency ablation for hepatocellular carcinoma is a minimally invasive therapy, there are some complications reported; major complications include hemorrhage (0.477%), hepatic injuries (1.690%), and extrahepatic organ injuries (0.691%). We, for the first time, described a rare complication of delayed bronchobiliary fistula and cholangiolithiasis in common bile duct following radio frequency ablation and the salvage treatment in a patient with chronic hepatitis B virus infection. Surgeons should be aware of severe and rare complications before deciding the ablation area and when performing radio frequency ablation, and should be aware of the relevant salvage treatment.