Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis

Chu, Andrew S.; Diaz, Rosalyn; Hui, Jia; Yanger, Kilangsungla; Zong, Yiwei; Alpini, Gianfranco; Stanger, Ben Z.; Wells, Rebecca G.

doi:10.1002/hep.24206

Cited by 193 publications

(153 citation statements)

References 90 publications

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“…A very similar conclusion was reached in a second study from the same group [32] A fourth study challenging EMT [34] employed lineage tracing generated by crossing the alphafetoprotein (AFP) Cre mouse with the ROSA26YFP stop mouse in order to trace the fate of any cell ever expressing AFP. This approach led to a genetic labeling of all cholangiocytes and hepatocytes, because all these epithelial cells derived from AFP-expressing precursor cells.…”

Section: Epithelial To Mesenchymal Transition (Emt) Process and Livermentioning

confidence: 65%

“…The real involvement of EMT as a pathogenic mechanism contributing to liver fibrogenesis in CLDs is then more than controversial, with accumulating evidence deposing against EMT from either hepatocytes or cholangiocytes [31][32][33][34][35][36]. Along these lines, an excellent very recent fate tracing study from the laboratory of Robert Schwabe, performed using a novel Cre-transgenic mouse that marks 99% of hepatic stellate cells, has shown that HSCs give rise to 82-96% of myofibroblasts in models of toxic, cholestatic and fatty liver disease [37].…”

Section: Epithelial To Mesenchymal Transition (Emt) Process and Livermentioning

confidence: 99%

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Cellular and molecular mechanisms in liver fibrogenesis

Novo

Cannito

Paternostro

et al. 2014

Archives of Biochemistry and Biophysics

178

194

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Section: Epithelial To Mesenchymal Transition (Emt) Process and Livermentioning

confidence: 65%

Section: Epithelial To Mesenchymal Transition (Emt) Process and Livermentioning

confidence: 99%

Cellular and molecular mechanisms in liver fibrogenesis

Novo

Cannito

Paternostro

et al. 2014

Archives of Biochemistry and Biophysics

178

194

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“…The possibility that cholangiocytes could also feed the pool of stroma myofibroblasts has been refuted in different models of fibrosis [132] and more recently in a murine model of xenografted tumors [133]. CAFs have a crucial role in favoring CCA progression, and more particularly in promoting EMT, through interactive autocrine and paracrine signaling pathways [68,131].…”

Section: Cancer-associated Fibroblasts (Cafs) and Hepatic Stellate Cementioning

confidence: 99%

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Vaquero

Guedj

Clapéron

et al. 2017

Journal of Hepatology

124

122

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Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis due to its late clinical presentation and the lack of effective non-surgical therapies. Unfortunately, most of the patients are not eligible for curative surgery owing to the presence of metastases at the time of diagnosis. Therefore, it is important to understand the steps leading to cell dissemination in patients with CCA. To metastasize from the primary site, cancer cells must acquire migratory and invasive properties by a cell plasticity-promoting phenomenon known as epithelial-mesenchymal transition (EMT). EMT is a reversible dynamic process by which epithelial cells gradually adopt structural and functional characteristics of mesenchymal cells, and has lately become a center of attention in the field of metastatic dissemination. In the present review, we aim to provide an extensive overview of the current clinical data and the prognostic value of different EMT markers that have been analyzed in CCA. We summarize all the regulatory networks implicated in EMT from the membrane receptors to the main EMT-inducing transcription factors (SNAIL, TWIST and ZEB). Furthermore, since a tumor is a complex structure not exclusively formed by tumor cells, we also address the prominent role of the main cell types of the desmoplastic stroma that characterizes CCA in the regulation of EMT. Finally, we discuss the therapeutic considerations and difficulties faced to develop an effective anti-EMT treatment due to the redundancies and bypasses among the pathways regulating EMT. 4Key Point Box -EMT is an early event of metastasis that endows tumor cells with invasive properties enabling them to spread toward other territories.-EMT contributes to CCA progression and chemoresistance.-The three families of transcription factors that regulate epithelial and mesenchymal marker expression during EMT (SNAIL, TWIST and ZEB) contribute to CCA progression.-Cells of CCA microenvironment, and not only cancer cells, lead to the activation of EMT.

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“…1D). Activated HSCs are the major source of myofibroblasts in the liver during hepatic fibrosis (15)(16)(17). Thus, the primary activated HSCs were further isolated from saline/TAA-treated fibrotic livers according to published protocols (11,12).…”

Section: Mir-21 Was Predominantly Up-regulated In Hscs Inmentioning

confidence: 99%

The Autoregulatory Feedback Loop of MicroRNA-21/Programmed Cell Death Protein 4/Activation Protein-1 (MiR-21/PDCD4/AP-1) as a Driving Force for Hepatic Fibrosis Development

Zhang

Zha

et al. 2013

Journal of Biological Chemistry

112

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Background: MicroRNA-21 is important in hepatic fibrosis development, but the mechanism is unclear. Results: MicroRNA-21 is predominantly up-regulated in activated hepatic stellate cells and could form a double negative feedback loop that links fibrogenic machinery. Conclusion:The microRNA-21-mediated loop is a main driving force for hepatic fibrosis progression. Significance: It suggests a mechanism for how microRNA-21 contributes to hepatic fibrosis.Sustained activation of hepatic stellate cells (HSCs) leads to hepatic fibrosis, which is characterized by excessive collagen production, and for which there is no available drug clinically. Despite tremendous progress, the cellular activities underlying HSC activation, especially the driving force in the perpetuation stage, are only partially understood. Recently, microRNA-21 (miR-21) has been found to be prevalently up-regulated during fibrogenesis in different tissues, although its detailed role needs to be further elucidated. In the present study, miR-21 expression was examined in human cirrhotic liver samples and in murine fibrotic livers induced by thioacetamide or carbon tetrachloride. A dramatic miR-21 increase was noted in activated HSCs. We further found that miR-21 maintained itself at constant high levels by using a microRNA-21/programmed cell death protein 4/activation protein-1 (miR-21/PDCD4/AP-1) feedback loop. Disrupting this loop with miR-21 antagomir or AP-1 inhibitors significantly suppressed fibrogenic activities in HSCs and ameliorated liver fibrosis. In contrast, reinforcing this loop with small interfering RNA (siRNA) against PDCD4 promoted fibrogenesis in HSCs. Further analysis indicated that the up-regulated miR-21 promoted the central transforming growth factor-␤ (TGF-␤) signaling pathway underlying HSC activation. In summary, we suggest that the miR-21/PDCD4/AP-1 autoregulatory loop is one of the main driving forces for hepatic fibrosis progression. Targeting this aberrantly activated feedback loop may provide a new therapeutic strategy and facilitate drug discovery against hepatic fibrosis.Hepatic fibrosis is a wound healing process in response to chronic liver injuries that leads to unbalanced extracellular matrix (ECM) 3 deposition and resolution. The persistent activation of wound healing responses causes quantitative and qualitative changes in the ECM components and could finally distort liver parenchyma and vascular architecture, which could impair liver function and potentially lead to liver failure and hepatocellular carcinoma. Following liver injury, quiescent hepatic stellate cells (HSCs) transdifferentiate into myofibroblast-like cells that are characterized by the expression of smooth muscle ␣-actin (␣-SMA) and enhanced production of ECM (1). Despite the tremendous progress in understanding the mechanisms during fibrogenesis, the driving force underlying the persistent fibrogenic activities is still only partially understood.Extensive studies have suggested the central role of feedback networks in dictating disease progressi...

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Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis

Cited by 193 publications

References 90 publications

Cellular and molecular mechanisms in liver fibrogenesis

Cellular and molecular mechanisms in liver fibrogenesis

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

The Autoregulatory Feedback Loop of MicroRNA-21/Programmed Cell Death Protein 4/Activation Protein-1 (MiR-21/PDCD4/AP-1) as a Driving Force for Hepatic Fibrosis Development

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