Molecular mechanisms controlling the phenotype and the EMT/MET dynamics of hepatocyte

Abstract

The complex spatial and paracrine relationships between the various liver histotypes are essential for proper functioning of the hepatic parenchymal cells. Only within a correct tissue organization, in fact, they stably maintain their identity and differentiated phenotype. The loss of histotype identity, which invariably occurs in the primary hepatocytes in culture, or in vivo in particular pathological conditions (fibrosis and tumours), is mainly because of the phenomenon of epithelial-to-mesenchymal transition (EMT). The EMT process, that occurs in the many epithelial cells, appears to be driven by a number of general, non-tissue-specific, master transcriptional regulators. The reverse process, the mesenchymal-to-epithelial transition (MET), as yet much less characterized at a molecular level, restores specific epithelial identities, and thus must include tissue-specific master elements. In this review, we will summarize the so far unveiled events of EMT/MET occurring in liver cells. In particular, we will focus on hepatocyte and describe the pivotal role in the control of EMT/MET dynamics exerted by a tissue-specific molecular mini-circuitry. Recent evidence, indeed, highlighted as two transcriptional factors, the master gene of EMT Snail, and the master gene of hepatocyte differentiation HNF4α, exhorting a direct reciprocal repression, act as pivotal elements in determining opposite cellular outcomes. The different balances between these two master regulators, further integrated by specific microRNAs, in fact, were found responsible for the EMT/METs dynamics as well as for the preservation of both hepatocyte and stem/precursor cells identity and differentiation. Overall, these findings impact the maintenance of stem cells and differentiated cells both in in vivo EMT/MET physio-pathological processes as well as in culture.

TGFbeta Induces Binucleation/Polyploidization in Hepatocytes through a Src-Dependent Cytokinesis Failure

“…Interestingly, among the tested cytokines, TGFbeta1 induced, together with a morphological epithelial-to-mesenchymal transition (EMT) as expected and previously described [22–24], also a weighty rate of binucleation compared to untreated cells (23,3±3% in TGFbeta1-treated versus 2,1±1,8% in untreated cells) (Fig 1A, Fig 1B and S1 Fig, upper panels, and Fig 1C). …”

Changes in microRNA expression during disease progression in patients with chronic viral hepatitis

“…The altered expression of miRNAs in liver fibrosis and necrosis that was observed in this study is in agreement with their functional role and could be further investigated as potential biomarkers of liver fibrosis [41] and cell death [42,43]. Assessment of these and other miRNAs might be done in formalin-fixed paraffin embedded (FFPE) samples, thus allowing to select a larger group of patients for validation studies, as well as to analyze retrospectively samples from the same patient in order to identify miRNAs more directly related to progression of the process and, in the cases of treated patients, with regression of the architectural changes.…”

Epigenetic control of EMT/MET dynamics: HNF4α impacts DNMT3s through miRs-29

“…Wide evidence demonstrated that the orphan nuclear receptor hepatocyte nuclear factor 4-α (HNF4α), master regulator of hepatocyte differentiation and hepatic epithelium formation [13,14], also acts as a master regulator of MET (for review [15]). Notably, a role for HNF4α as a direct repressor of master EMT regulators and mesenchymal genes was recently unveiled, thus providing evidence for its pivotal function for both the regulation of the dynamic process of MET and the maintenance of a stable epithelial phenotype [16].…”