TITLE ! : Which in vitro models could be best used to study hepatocyte polarity ?

The correct functioning of the liver is ensured by the setting and the maintenance of hepatocyte polarity. The complex polarity of hepatocyte is characterized by the existence of several basolateral and apical poles per cell. Many in vitro models are available for studying hepatocyte polarity. But which are the more suitable? To answer this question, we wished to identify criteria which determine the typical hepatocyte polarity. Therefore, we compiled a battery of protein markers of membrane domains in rat hepatocytes and looked for their involvement in hepatocytic functions. Then, we focused on the relationship between hepatic functions and the cytoskeleton, Golgi apparatus and endoplasmic reticulum. Subsequently, we compared different cell lines expressing hepatocyte polarity. Finally, to demonstrate the usefulness of some of these lines, we presented new data on reticulum organization in relation to polarity. INTRODUCTION Although the Ancient Greeks already knew that the liver is able to regenerate, nowadays many people are still working hard to understand how this main organ functions. The liver is made up of 60% hepatocytes that produce 90% of the whole hepatic proteins and which are responsible for most of the main liver functions such as bile production, detoxification... As all epithelial cells, hepatocytes must be polarized to be functional. This implies the formation of specific membrane domains and special cytoskeletal and endoplasmic reticulum (ER) networks. Hepatocyte polarity is very peculiar and complex (Hubbard et al., 1994) compared to the so-called «!simple polarity!» of most epithelial cells such as intestinal cells (Figure 1). «!Simple!» polarized cells have one apical pole located at the cell apex and one basolateral pole corresponding to the remaining domain of the plasma membrane. In contrast, hepatocytes that are organized in plates in the liver have several apical and basolateral poles. In contact with the external environment, the apical poles of frontfacing and adjacent hepatocytes form a continuous network of bile canaliculi (BC), into which bile is secreted. In contact with the blood, the basal membrane domain called sinusoidal pole, secretes various components -proteins, drugsinto the circulation and takes up recycled biliary salts. In both types of polarized cells, the tight junctions make the frontier between apical and lateral poles. The first studies on hepatocytes were performed with isolated perfused organ and subcellular fractionations (Bartles et al., 1987). Later, easier in vitro models were obtained by enzymatic digestion of the liver!: freshly isolated hepatocytes induced to repolarize (Musat et al., 1993) and hepatocytes isolated as couplets that keep a bile canalicular space between the two cells (Graf et al., 1984). Both models have been widely used to study bile secretion (Graf and Boyer, 1990), protein trafficking (Maurice et al., 1988) and calcium waves (Combettes et al., 1994). However, variations