New Methods in Tissue Engineering: Improved Models for Viral Infection

Ramanan, Vyas; Scull, Margaret A.; Sheahan, Timothy P.; Rice, Charles M.; Bhatia, Sangeeta N.

doi:10.1146/annurev-virology-031413-085437

Cited by 23 publications

(12 citation statements)

References 215 publications

(243 reference statements)

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“…Moreover, because the human hepatitis virus cannot infect mice or rats, a rodent model of virus induced hepatitis is currently unavailable. Furthermore, the cell culture models of virus infection, including infection by hepatotropic viruses, cannot be satisfactorily manipulated [ 20 ]. Because both in vitro and in vivo models of liver cancer pathogenesis are limited by their restricted host range and hepatotropism, LPS-induced inflammation is an acceptable alternative for investigating the mechanisms of inflammation-induced hepatopathogenesis [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Inflammation Promotes Expression of Stemness-Related Properties in HBV-Related Hepatocellular Carcinoma

Chang

Chen

et al. 2016

PLoS ONE

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The expression of cancer stemness is believed to reduce the efficacy of current therapies against hepatocellular carcinoma (HCC). Understanding of the stemness-regulating signaling pathways incurred by a specific etiology can facilitate the development of novel targets for individualized therapy against HCC. Niche environments, such as virus-induced inflammation, may play a crucial role. However, the mechanisms linking inflammation and stemness expression in HCC remain unclear. Here we demonstrated the distinct role of inflammatory mediators in expressions of stemness-related properties involving the pluripotent octamer-binding transcription factor 4 (OCT4) in cell migration and drug resistance of hepatitis B virus-related HCC (HBV-HCC). We observed positive immunorecognition for macrophage chemoattractant protein 1 (MCP-1)/CD68 and OCT4/NANOG in HBV-HCC tissues. The inflammation-conditioned medium (inflamed-CM) generated by lipopolysaccharide-stimulated U937 human leukemia cells significantly increased the mRNA and protein levels of OCT4/NANOG preferentially in HBV-active (HBV+HBsAg+) HCC cells. The inflamed-CM also increased the side population (SP) cell percentage, green fluorescent protein (GFP)-positive cell population, and luciferase activity of OCT4 promoter-GFP/luciferase in HBV-active HCC cells. Furthermore, the inflamed-CM upregulated the expressions of insulin-like growth factor-I (IGF-I)/IGF-I receptor (IGF-IR) and activated IGF-IR/Akt signaling in HBV-HCC. The IGF-IR phosphorylation inhibitor picropodophyllin (PPP) suppressed inflamed-CM-induced OCT4 and NANOG levels in HBV+HBsAg+ Hep3B cells. Forced expression of OCT4 significantly increased the secondary sphere formation and cell migration, and reduced susceptibility of HBV-HCC cells to cisplatin, bleomycin, and doxorubicin. Taking together, our results show that niche inflammatory mediators play critical roles in inducing the expression of stemness-related properties involving IGF-IR activation, and the upregulation of OCT4 contributes to cancer migration and drug resistance of HBV-HCC cells. Findings in this paper would provide potential targets for a therapeutic strategy targeting on inflammatory environment for HBV-HCC.

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Section: Discussionmentioning

confidence: 99%

Inflammation Promotes Expression of Stemness-Related Properties in HBV-Related Hepatocellular Carcinoma

Chang

Chen

et al. 2016

PLoS ONE

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“…However, the majority of hepatoma cell lines do not elicit a strong immune response and IFNL expression. Novel model systems including stem cell derived hepatocytes [106][107][108] and tissue engineering systems [109] might in the future allow to more faithfully mimic host responses to hepatotropic virus infection.…”

Section: Ifnl In In Vitro Models Of Hepatitis C In Line With Observamentioning

confidence: 99%

The Role of Type III Interferons in Hepatitis C Virus Infection and Therapy

Bruening

Weigel

Gerold

2017

Journal of Immunology Research

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The human interferon (IFN) response is a key innate immune mechanism to fight virus infection. IFNs are host-encoded secreted proteins, which induce IFN-stimulated genes (ISGs) with antiviral properties. Among the three classes of IFNs, type III IFNs, also called IFN lambdas (IFNLs), are an essential component of the innate immune response to hepatitis C virus (HCV). In particular, human polymorphisms in IFNL gene loci correlate with hepatitis C disease progression and with treatment response. To date, the underlying mechanisms remain mostly elusive; however it seems clear that viral infection of the liver induces IFNL responses. As IFNL receptors show a more restricted tissue expression than receptors for other classes of IFNs, IFNL treatment has reduced side effects compared to the classical type I IFN treatment. In HCV therapy, however, IFNL will likely not play an important role as highly effective direct acting antivirals (DAA) exist. Here, we will review our current knowledge on IFNL gene expression, protein properties, signaling, ISG induction, and its implications on HCV infection and treatment. Finally, we will discuss the lessons learnt from the HCV and IFNL field for virus infections beyond hepatitis C.

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“…While this can certainly also be seen as an advantage by allowing the study of epithelial interactions without possible confounding effects from other cell types, it can also be seen as a limitation. Co-cultures and tissue engineering approaches will generate more complex stem cell-derived tissues which will allow the study of interactions with immune cells or other cell types (reviewed in Ramanan et al, 2014). For example, recently an exciting 3D model of human colon has been published, repopulating decellularized colonic mucosa with modified organoidderived epithelial cells, endothelial cells and myofibroblasts (Chen et al, 2016).…”

Section: Anaerobic Bacteriamentioning

confidence: 99%