Epithelial–Mesenchymal Transition: From Molecular Mechanisms, Redox Regulation to Implications in Human Health and Disease

Abstract

Epithelial to mesenchymal transition (EMT) is a fundamental process, paradigmatic of the concept of cell plasticity, that leads epithelial cells to lose their polarization and specialized junctional structures, to undergo cytoskeleton reorganization, and to acquire morphological and functional features of mesenchymal-like cells. Although EMT has been originally described in embryonic development, where cell migration and tissue remodeling have a primary role in regulating morphogenesis in multicellular organisms, recent literature has provided evidence suggesting that the EMT process is a more general biological process that is also involved in several pathophysiological conditions, including cancer progression and organ fibrosis. This review offers first a comprehensive introduction to describe major relevant features of EMT, followed by sections dedicated on those signaling mechanisms that are known to regulate or affect the process, including the recently proposed role for oxidative stress and reactive oxygen species (ROS). Current literature data involving EMT in both physiological conditions (i.e., embryogenesis) and major human diseases are then critically analyzed, with a special final focus on the emerging role of hypoxia as a relevant independent condition able to trigger EMT.

Cellular and molecular mechanisms in liver fibrogenesis

“…A very close scenario was confirmed in the same model of BDL (rat and murine) by a series of elegant studies from the group of Anna Mae Diehl [17], the most relevant being able to describe an apparently clear cause-effect relationships among EMT of cholangiocytes, appearance of portal MFs and biliary fibrosis as well as the closely related major involvement of Hedgehog signaling pathway. Morphological evidence for EMT of cholangiocytes was also described in liver biopsies from human patients affected by primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC) or biliary atresia [17,24]. In addition, the relevance of Hedgehog and TGFβ1-Smad2/3 signaling was reported also in human patients [17,24].…”

“…In particular, EMT has been proposed to contribute to fibrosis in those chronic conditions characterized by uncontrolled activation of wound-healing response and progressive fibrogenesis, then including also CLD. Pertinent to this review, several studies [reviewed in 17,24], have proposed that pro-fibrogenic cells, in addition to the cellular sources already mentioned, may originate in CLD through EMT involving either cholangiocytes or hepatocytes.…”

“…Morphological evidence for EMT of cholangiocytes was also described in liver biopsies from human patients affected by primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC) or biliary atresia [17,24]. In addition, the relevance of Hedgehog and TGFβ1-Smad2/3 signaling was reported also in human patients [17,24]. More recently, Notch signalinghas been also implicated in EMT and liver fibrosis based on the reported action of the γ-secretase inhibitor DAPT that, by inhibiting Notch signaling, blocked an EMT-like transition in both primary mouse HSCs and a rat HSC cell line as well as inhibited HSC activation and attenuated CCl 4 -induced rat liver fibrosis [28,29].…”

“…In particular, epithelial cells undergoing EMT lose their polarization and specialized junctional structures, undergo cytoskeleton reorganization, and to acquire morphological and functional features of mesenchymal-like cells, including the ability to migrate and to produce and secrete components of the extracellular matrix [23][24]. EMT and the related opposite process of MET (mesenchymal to epithelial transition) have been originally described in embryonic development (where cell migration and tissue remodeling have a primary role in regulating morphogenesis).…”

“…EMT and the related opposite process of MET (mesenchymal to epithelial transition) have been originally described in embryonic development (where cell migration and tissue remodeling have a primary role in regulating morphogenesis). More recent literature data have provided evidence suggesting that the EMT process may also have a significant role in cancer progression and also organ fibrosis [23][24]. In particular, EMT has been proposed to contribute to fibrosis in those chronic conditions characterized by uncontrolled activation of wound-healing response and progressive fibrogenesis, then including also CLD.…”