HCV derived from sera of HCV-infected patients induces pro-fibrotic effects in human primary fibroblasts by activating GLI2

Granato, Marisa; Zompetta, Claudia; Vescarelli, Enrica; Rizzello, Celeste; Cardi, Antonio; Valia, Sandro; Antonelli, Guido; Marchese, Cinzia; Torrisi, Maria Rosaria; Faggioni, Alberto; Cirone, Mara

doi:10.1038/srep30649

Cited by 25 publications

(23 citation statements)

References 54 publications

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“…HCV can directly infect human skin fibroblasts and induce the expression of pro-fibrotic proteins such as vimentin, collagen, and α-SMA by activating GLI2 (glioma-associated oncogene family zinc finger 2), which has been previously linked to organ fibrosis [53,54]. Since HSCs are considerably different from skin fibroblasts [55], this finding should also be confirmed in HSCs.…”

Section: Hcv-mediated Liver Fibrosismentioning

confidence: 91%

Origin and role of hepatic myofibroblasts in hepatocellular carcinoma

et al. 2020

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Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the second leading cause of cancer-related death worldwide. Fibrosis and cirrhosis are important risk factors for the development of HCC. Hepatic myofibroblasts are the cells responsible for extracellular matrix deposition, which is the hallmark of liver fibrosis. It is believed that myofibroblasts are predominantly derived from hepatic stellate cells (HSCs), also known as Ito cells. Nevertheless, depending on the nature of insult to the liver, it is thought that myofibroblasts may also originate from a variety of other cell types such as the portal fibroblasts (PFs), fibrocytes, hepatocytes, hepatic progenitor cells (HPCs), and mesothelial cells. Liver myofibroblasts are believed to transform into cancer-associated fibroblasts (CAFs) while HCC is developing. There is substantial evidence suggesting that activated HSCs (aHSCs)/cancer-associated fibroblasts (CAFs) may play an important role in HCC initiation and progression. In this paper, we aim to review current literature on cellular origins of myofibroblasts with a focus on hepatitis B virus (HBV)-and hepatitis C virus (HCV)-induced hepatic fibrosis. We also address the role of aHSCs/CAFs in HCC progression through the regulation of immune cells as well as mechanisms of evolvement of drug resistance.

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Section: Hcv-mediated Liver Fibrosismentioning

confidence: 91%

Origin and role of hepatic myofibroblasts in hepatocellular carcinoma

et al. 2020

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“…Recently published literature describes Hh pathway inhibitors as the following three categories: inhibitors targeting Smo, including nature compound (cyclopamine) and synthetic small molecules (vismodegib, sonidegib, IPI-926, BMS-833923, PF-04449913, SANT1–4, Cur61414, MRT-10); strategies to target the upstream N-Shh ligand, including Robotniknin and anti-Shh 5E1; and inhibitors targeting the downstream transcription factors Gli1 and Gli2, including Darinaparsin, GANT-61/58, HPI-1, and Forskolin ( 90 ). Various in vivo and in vitro studies demonstrated that some of these Hh pathway inhibitors, such as vismodegib ( 91 ), sonidegib ( 92 ), Forskolin ( 93 ), GANT-61 ( 94 ), GANT-58 ( 95 ), and cyclopamine ( 96 ), are capable of inhibiting or reversing the progression of liver fibrosis. Moreover, modulating repair-related inflammation response during the liver injury and repair is one of the important mechanisms of action for anti-fibrotic effect of these Hh pathway inhibitors.…”

Section: Targeting Hh Signaling Pathway For Anti-fibrotic Therapy Thrmentioning

confidence: 99%

The Injury-Related Activation of Hedgehog Signaling Pathway Modulates the Repair-Associated Inflammation in Liver Fibrosis

Shen

2017

Front. Immunol.

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Liver fibrosis is a wound healing response initiated by inflammation responding for different iterative parenchymal damages caused by diverse etiologies. Immune cells, which exert their ability of either inducing injury or promoting repair, have been regarded as crucial participants in the fibrogenic response. A characteristic feature of the fibrotic microenvironment associated with chronic liver injury is aberrant activation of hedgehog (Hh) signaling pathway. Growing evidence from a number of different studies in vivo and in vitro has indicated that immune-mediated events involved in liver fibrogenesis are regulated by Hh signaling pathway. In this review, we emphasize the impacts of injury-activated Hh signaling on liver fibrogenesis through modulating repair-related inflammation and focus on the regulatory action of aberrant Hh signaling on repair-related inflammatory responses mediated by hepatic classical and non-classical immune cell populations in the progression of liver fibrosis. Moreover, we also assess the potentiality of Hh pathway inhibitors as good candidates for anti-fibrotic therapeutic agents because of their immune regulation actions for fibrogenic liver repair. The identification of immune-modulatory mechanisms of Hh signaling pathway underlying the fibrotic process of chronic liver diseases might provide a basis for Hh-centered therapeutic strategies for liver fibrosis.

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“…Autophagy is articulated in several steps that go from autophagosome formation and elongation to their degradation into the lysosomes. It is involved in a variety of cellular functions including cell death, survival and differentiation, depending on the cell types and on the extent to which the process is activated [18][19][20]. Autophagy upregulation may help cells to cope with increased demands induced by stressful conditions by degrading and eventually recycling misfolded and long-lived proteins and damaged organelles [21].…”

Section: Introductionmentioning

confidence: 99%

EBV reduces autophagy, intracellular ROS and mitochondria to impair monocyte survival and differentiation

et al. 2018

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EBV has been reported to impair monocyte in vitro differentiation into dendritic cells (DCs) and reduce cell survival. In this study, we added another layer of knowledge to this topic and showed that these effects correlated with macroautophagy/autophagy, ROS and mitochondrial biogenesis reduction. Of note, autophagy and ROS, although strongly interconnected, have been separately reported to be induced by CSF2/GM-CSF (colony stimulating factor 2) and required for CSF2-IL4-driven monocyte in vitro differentiation into DCs. We show that EBV infects monocytes and initiates a feedback loop in which, by inhibiting autophagy, reduces ROS and through ROS reduction negatively influences autophagy. Mechanistically, autophagy reduction correlated with the downregulation of RAB7 and ATG5 expression and STAT3 activation, leading to the accumulation of SQSTM1/p62. The latter activated the SQSTM1-KEAP1-NFE2L2 axis and upregulated the anti-oxidant response, reducing ROS and further inhibiting autophagy. ROS decrease correlated also with the reduction of mitochondria, the main source of intracellular ROS, achieved by the downregulation of NRF1 and TFAM, mitochondrial biogenesis transcription factors. Interestingly, mitochondria supply membranes and ATP required for autophagy execution, thus their reduction may further reduce autophagy in EBV-infected monocytes. In conclusion, this study shows for the first time that the interconnected reduction of autophagy, intracellular ROS and mitochondria mediated by EBV switches monocyte differentiation into apoptosis, giving new insights into the mechanisms through which this virus reduces immune surveillance.

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HCV derived from sera of HCV-infected patients induces pro-fibrotic effects in human primary fibroblasts by activating GLI2

Cited by 25 publications

References 54 publications

Origin and role of hepatic myofibroblasts in hepatocellular carcinoma

Origin and role of hepatic myofibroblasts in hepatocellular carcinoma

The Injury-Related Activation of Hedgehog Signaling Pathway Modulates the Repair-Associated Inflammation in Liver Fibrosis

EBV reduces autophagy, intracellular ROS and mitochondria to impair monocyte survival and differentiation

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