Biol. Chem., Vol. 390, pp. 1003–1012, October 2009 • Copyright  by Walter de Gruyter • Berlin • New York. DOI 10.1515/BC.2009.121 2009/222 Article in press - uncorrected proof Review Hepatic and pancreatic stellate cells in focus Claus Kordes, Iris Sawitza and Dieter Ha ¨ ussinger* Clinic of Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Moorenstraße 5, D-40225 Du ¨ sseldorf, Germany *Corresponding author e-mail: haeussin@uni-duesseldorf.de Abstract Stellate cells are vitamin A-storing cells of liver and pancreas and have been described in all vertebrates ranging from lampreys (primitive fish) to humans, dem- onstrating their major importance. This cell type is thought to contribute to fibrosis, a condition character- ized by an excess deposition of extracellular matrix pro- teins. Recently, the expression of stem/progenitor cell markers, such as CD133 (prominin-1) and Oct4, was dis- covered in hepatic stellate cells (HSCs) of rats. Moreover, HSCs possess signaling pathways important for main- tenance of stemness and cell differentiation, such as hedgehog, b-catenin-dependent Wnt, and Notch signal- ing, and are resistant to CD95-mediated apoptosis. In analogy to a stem cell niche, some characteristics of qui- escent HSC are maintained by aid of a special micro- environment located in the space of Disse ´. Finally, stellate cells display a differentiation potential as inves- tigated in vitro and in vivo. Collectively all these proper- ties are congruently found in stem/progenitor cells and support the concept that stellate cells are undifferenti- ated cells, which might play an important role in liver regeneration. The present review highlights findings relat- ed to this novel aspect of stellate cell biology. Keywords: liver regeneration; liver stem cells; origin of stellate cells; pancreatic stellate cells (PSCs). Introduction: identification of stellate cells Vitamin A-storing cells have been found in several organs of vertebrates, such as liver, pancreas, kidney, intestine, lung, spleen, uterus, and skin (Wake, 1971, 1980; Watari et al., 1982; Nagy et al., 1997). Among cells that contain retinoids the stellate-shaped cells of the liver were inten- sively studied. These hepatic stellate cells (HSCs) display marked lipid droplets (Figure 1A) and store vitamin A mainly as retinyl palmitate, which increases with age as investigated in rats (Hendriks et al., 1985). The cellular vitamin A content, visible after excitation with UV light by rapidly fading fluorescence light, is one of the best stel- late cell markers, but also some intermediate filament proteins are useful to identify stellate cells. In rodents, many HSCs synthesize the filamentous proteins desmin and glial fibrillary acidic protein (GFAP; Yokoi et al., 1984; Gard et al., 1985) (Figure 2A, C). In contrast to this, qui- escent stellate cells of the normal human liver are devoid of desmin expression (Schmitt-Gra ¨ ff et al., 1991), where- as GFAP is primarily observed in a small subpopulation of HSCs in the vicinity of the portal tracts (Hautekeete and Geerts, 1997). Obviously the gene expression profile of HSCs varies between species, which led to the con- cept of a diffuse stellate cell system in mammals (Zhao and Burt, 2007). Another intermediate filament protein congruently found in human and rat stellate cells is vimentin (Ahmed et al., 1991; Casini et al., 1993). How- ever, isolated HSCs from humans and rodents cultured on plastic dishes develop into contractile myofibroblast- like cells that synthesize a-smooth muscle actin (a-SMA) and extracellular matrix proteins, such as collagen type I. Owing to these properties of myofibroblast-like cells, HSCs are regarded to be involved in formation of liver fibrosis (Friedman, 2008). The same concept was evolved for pancreatic stellate cells (PSCs) that were first isolated from rats after application of a vitamin A rich diet (Apte et al., 1998; Bachem et al., 1998). Normally, PSCs contain substantially lower retinoid levels than their hepatic counterpart (Ikejiri, 1990), a situation that ham- pers their identification. Also, stellate cells of the rat liver store variable amounts of vitamin A and a subset is nega- tive for desmin (Ramm et al., 1995). Desmin-negative HSCs are found especially in the pericentral zone (Figure 2B), and desmin-positive in the periportal zone of the liver (Ballardini et al., 1994) (Figure 2A). This means that even in a single organism HSCs are heterogeneous, showing differential gene expression and cell morpholo- gy depending on their relative position from periportal to pericentral zone of the liver (Geerts, 2001). The zonal organization of the liver, initially described for the hepatic glutamine and ammonia metabolism (Ha ¨ ussinger, 1983, 1990; Ha ¨ ussinger and Schliess, 2007), is also visible through the distinct synthesis of the enzyme glutamine synthetase by liver parenchymal cells that surround the central vein (Gebhardt and Mecke, 1983; Go ¨ rg et al., 2005) (Figure 2D, E). The zonal expression of these genes is at least in part caused by b-catenin-dependent or canonical Wnt signaling that inversely controls the genet- ic programs of perivenous and periportal cells (Benha- mouche et al., 2006). The origin of stellate cells An additional level of complexity is reached when the gene expression pattern of HSCs is analyzed, because they express genes of all three embryonic germ layers (Geerts, 2004). This impedes analyses of the embryonic Brought to you by | University of Rochester Authenticated | 128.151.244.46 Download Date | 4/16/13 5:50 PM