Hepatic differentiation of mesenchymal stem cells: in vitro strategies.

Recently, evidence has been provided that mesenchymal stem/progenitor cells (MSC) from various sources (bone marrow, adipose tissue, skin, placenta, umbilical cord) could occasionally overcome lineage borders and differentiate into endodermal (hepatocytes) and ectodermal (neural cells) cell types in vitro. Whereas unidirectional differentiation into other mesenchymal cell types, including adipocytes, chondrocytes, and osteoblasts, readily occurs in the presence of a simple cocktail of growth factors and nutrients, successful bypassing of lineage borders mainly depends on multistep processes in a coordinated signaling network. Here, we provide a reproducible basic methodology to differentiate adult MSC into functional hepatocytes in a sequential and time-dependent way. In addition, focus lies on the functional characterization of MSC-derived hepatocyte-like cells. In particular, we provide a detailed modus operandi to measure the inducible cytochrome P450 (CYP)-dependent activity of MSC-derived hepatocyte-like cells.

Histone deacetylase inhibition and the regulation of cell growth with particular reference to liver pathobiology.

The transcriptional activity of genes largely depends on the accessibility of specific chromatin regions to transcriptional regulators. This process is controlled by diverse post-transcriptional modifications of the histone amino termini of which reversible acetylation plays a vital role. Histone acetyltransferases (HATs) are responsible for the addition of acetyl groups and histone deacetylases (HDACs) catalyse the reverse reaction. In general, though not exclusively, histone acetylation is associated with a positive regulation of transcription, whereas histone deacetylation is correlated with transcriptional silencing. The elucidation of unequivocal links between aberrant action of HDACs and tumorigenesis lies at the base of key scientific importance of these enzymes. In particular, the potential benefit of HDAC inhibition has been confirmed in various tumour cell lines, demonstrating antiproliferative, differentiating and pro-apoptotic effects. Consequently, the dynamic quest for HDAC inhibitors (HDIs) as a new class of anticancer drugs was set off, resulting in a number of compounds that are currently evaluated in clinical trials. Ironically, the knowledge with respect to the expression pattern and function of individual HDAC isoenzymes remains largely elusive. In the present review, we provide an update of the current knowledge on the involvement of HDACs in the regulation of fundamental cellular processes in the liver, being the main site for drug metabolism within the body. Focus lies on the involvement of HDACs in the regulation of growth of normal and transformed hepatocytes and the transdifferentiation process of stellate cells. Furthermore, extrapolation of our present knowledge on HDAC functionality towards innovative treatment of malignant and non-malignant, hyperproliferative and inflammatory disorders is discussed.

Histone deacetylase inhibitors as potent modulators of cellular contacts.

Histone deacetylase inhibitors are nowadays considered as promising anti-cancer drugs, as they interfere with several key steps of tumor development and progression, both in vitro and in vivo. Less attention has been paid to their impact on cell junctions. Nevertheless, cell junctions are gatekeepers in the management of tissue homeostasis, and their aberrant expression and functioning is observed in all aspects of cancer biology. The present review provides a state of the art of the current knowledge concerning the effects of histone deacetylase inhibitors on cell junctions. Besides an updated theoretical basis, we also exemplify its actual relevance in cancer therapy.