Growth control and cell cycle progression in cultured hepatocytes

In contrast to unicellular organisms such as yeast or bacteria for which there is strong selective pressure for each individual cell to grow and divide as rapidly as possible, the cells of multicellular animals are specialized members of a complex society. Delicately adjusted and highly specific controls exist to govern the proliferation of each type of cell according to need and rates of renewal that greatly vary from one tissue to another. Thus, while some tissues are composed of permanently growth-arrested differentiated cells with a long life-span, others are formed by continuously renewing cells, which die after reaching a terminal differentiated stage. The liver is an intriguing example of a tissue between these two categories, in which normal rates of renewal are maintained albeit at a very low level. This organ can be stimulated to produce new cells at a higher rate by surgically removing a large mass of tissue or by destroying the cells by toxins in the diet. Renewal in this tissue takes place by simple duplication of existing differentiated hepatocytes that divide to give pairs of daughter cells of the same type. This process, triggered by environmental signals such as growth factors, is associated with a transient change of phenotype involving numerous genes that are regulated by a complex combination of control mechanisms: those responsible for mutually exclusive molecular events leading to differentiation or proliferation, and to survival or apoptosis. The regulatory mechanisms in hepatocytes may differ in part from those involved in differentiated cells of other tissues. This chapter updates data, derived from studies in primary culture, that have contributed to a better understanding of the sequences of the processes regulating hepatocyte proliferation during liver regeneration.