Histone Deacetylase Inhibition: A Differentiation Therapy for Cultured Primary Hepatocytes?

Histone deacetylase (HDAC) inhibitors are now widely recognized as powerful anticancer agents. Unlike conventional chemotherapeutics, they not only inhibit tumor growth and survival but also reinitiate differentiation processes. Surprisingly, little attention has been paid so far to their capacity as differentiating agents for primary non-malignant cells. Dedifferentiation, however, is a common pernicious event occurring in almost all primary epithelial cell cultures and limits their use in fundamental and applied research. In this review, we elaborate on the innovative concept of HDAC inhibition as a key tool in the development of functional long-term cultures of primary hepatocytes. The need for long-term hepatocyte-based in vitro models is high and underscored by the fact that (sub)-chronic liver toxicity testing still consumes an important number of animals and by recent changes in EU legislation (e.g. chemicals policy REACH and cosmetics Directive 2003/15/EC). In addition, many cell-based therapies would benefit from the availability of highly differentiated primary hepatocytes as well. We believe that the HDAC inhibition approach could be applicable to create stable, differentiated culture systems of other primary cell types as well. In addition, HDAC inhibitors, in combination with tissue-specific growth factors, can be used to generate tissue-specific cell types from stem cells.