Is it the end of the line for the EMT?

Abstract

E pithelial-to-mesenchymal transition (EMT) is an important biological concept that describes the reversible transition of differentiated epithelial cells into mesenchymal cells with increased motility and changes in gene expression. Three types of EMT have been proposed: Type 1 EMT describes the invasion of transition cells into the mesenchyme during development. Type 2 EMT describes the transition into mesenchymal cells, potentially including myofibroblasts during wound healing and repair. Type 3 EMT describes invasion of cancer cells, including those migrating into the circulation to generate distant metastases. 1Fibrosis studies conducted in different organs including the liver have demonstrated that myofibroblasts are the primary source of extracellular matrix.2 Myofibroblasts are immunophenotypically characterized by a stellate shape, expression of abundant pericellular matrix, and fibrotic genes (a-smooth muscle actin [a-SMA], nonmuscle myosin, fibronectin, vimentin).3 Ultrastructurally, myofibroblasts are defined by prominent rough endoplasmic reticulum, a Golgi apparatus producing collagen, peripheral myofilaments, fibronexus (no lamina), and gap junctions.3 Myofibroblasts are implicated in wound healing and fibroproliferative disorders. [4][5][6] In response to fibrogenic stimuli, such as transforming growth factor b1 (TGF-b1), myofibroblasts express a-SMA, secrete extracellular matrix (fibronectin, collagen type I and III), obtain high contractility, and change phenotype (production of the stress fibers). 7But where do these myofibroblasts come from? Hepatic stellate cells (HSCs) are considered to be a major source of fibrogenic myofibroblasts in the injured liver. Hepatic myofibroblasts may also originate from portal fibroblasts, 2 bone marrow-derived mesenchymal cells, and fibrocytes, 9,10 and by the transition of epithelial cells 11 and endothelial cells 12 to mesenchymal cells. What is the evidence for type 2 EMT being the etiology of the myofibroblasts in liver fibrosis? First, multiple studies in the kidney and in the lung were interpreted as showing EMT during fibrosis in those organs, and this concept was extrapolated to liver fibrosis (discussed in Zeisberg and Duffield 13 ). Second, primary cell culture studies have clearly demonstrated that cholangiocytes and hepatocytes undergo a change in the phenotype and gene expression toward a mesenchymal cell, especially after incubation with TGF-beta, which is the cytokine most closely associated with EMT.14 Third, immunohistochemical studies both in experimental and clinical liver fibrosis have reported the coexpression of mesenchymal markers (fibroblastspecific protein 1 [FSP1], a-SMA, vimentin, desmin) with the original epithelial markers (cytokeratin-19 for cholangiocytes and albumin for hepatocytes).15 These types of studies have been recently questioned, because the allegedly EMT-specific marker FSP1 (also called S100A4) has now been shown to be expressed by nonfibroblast cells in the liver, including by a subset of monocytes.16 Fourth, at lea...

Autophagy and senescence in fibrosing cholangiopathies

“…In fact, mesenchymal markers and Snail were expressed but CK19 and E-cadherin were not expressed in the cholangiocytes lining the remnants of extrahepatic bile ducts in BA, suggesting that these cholangiocytes were undergoing EMT [14]. However, there have been several reports against EMT in the liver as a source of myofibroblasts, using lineage tracing studies [131,132]. The surviving cholangiocytes expressing EMT markers on the remnants may produce the fibrogenic cytokine TGFb [133], thus activating periductal fibroblasts followed by the accumulation of an extracellular matrix and progressive fibrosis.…”

HDAC1 promoted migration and invasion binding with TCF12 by promoting EMT progress in gallbladder cancer

“…These include detachment of tumor cells from the primary tumor, intravasation into lymph and blood vessels, survival in the circulation, extravasation into target organs, and subsequent proliferation and induction of angiogenesis[26, 27]. In recent years, the development of molecular biology has led to the successful exploration and identification of biomarkers.…”

Hepatic Myofibroblasts in Liver Fibrogenesis

“…Clinical and experimental evidence indicates that under conditions of chronic liver injury, pro-fibrogenic MFs (mainly IF/MFs and, possibly, some P/MFs) may also originate from progressive recruitment of bone marrow-derived cells (Forbes et al, 2004;Kisseleva et al, 2006;Kallis et al, 2007;Henderson and Forbes, 2008;Friedman, 2008b;Parola et al 2008;Forbes & Parola, 2011;Kisseleva & Brenner, 2011). This extrahepatic source of MFs is at present believed to offer a significant although modest contribution to liver fibrogenesis.…”

“…This has generated an intense debate that the interested reader may find recapitulated in three recently published editorials (Wells, 2010;Popov and Schuppan, 2010;Kisseleva & Brenner, 2011).…”