Vitamin A‐Storing Cells (Stellate Cells)

Hepatic stellate cells (HSCs; also called as vitamin A‐storing cells, lipocytes, interstitial cells, fat‐storing cells, Ito cells) exist in the space between parenchymal cells and sinusoidal endothelial cells of the hepatic lobule, and store 80% of vitamin A in the whole body as retinyl palmitate in lipid droplets in the cytoplasm. In physiological conditions, these cells play pivotal roles in the regulation of vitamin A homeostasis; they express specific receptors for retinol‐binding protein (RBP), a binding protein specific for retinol, on their cell surface, and take up the complex of retinol and RBP by receptor‐mediated endocytosis. HSCs in Arctic animals such as polar bears and Arctic foxes store 20–100 times the levels of vitamin A found in human or rat. HSCs play an important role in the liver regeneration. A gradient of vitamin A‐storage capacity exists among the SCs in a hepatic lobule. The gradient was expressed as a symmetrical biphasic distribution starting at the periportal zone, peaking at the middle zone, and sloping down toward the central zone in the hepatic lobule. In pathological conditions such as liver fibrosis, HSCs lose vitamin A and synthesize a large amount of extracellular matrix (ECM) components including collagen, proteoglycan, and adhesive glycoproteins. Morphology of these cells also changes from the star‐shaped SCs to that of fibroblasts or myofibroblasts. The three‐dimensional structure of ECM components was found to regulate reversibly the morphology, proliferation, and functions of the HSCs. Molecular mechanisms in the reversible regulation of the SCs by ECM imply cell surface integrin‐binding to ECM components followed by signal transduction processes and then cytoskeleton assembly. SCs also exist in extrahepatic organs such as pancreas, lung, kidney, and intestine. Hepatic and extrahepatic SCs form the SC system.

Introduction

The hepatic lobule consists of parenchymal cells (PCs) and non‐parenchymal cells associated with the sinusoids: endothelial cells (ECs), Kupffer cells, pit cells, dendritic cells, and SCs (Bloom 1994, Wake 1971, Wake 1980) (Fig. 1). Sinusoidal endothelial cells (SECs) express lymphocyte costimulatory molecules (Kojima et al., 2001) and form the greater part of the extremely thin lining of the sinusoids, which are larger than ordinary capillaries and more irregular in shape. Kupffer cells are tissue macrophages and components of the diffuse mononuclear phagocyte system. They are usually situated on the endothelium with cellular processes extending between the underlying ECs. The greater part of their irregular cell surface is exposed to the blood in the lumen of the sinusoid. Pit cells are natural killer cells. Dendritic cells, located in the portal triad in human (Prickett et al., 1988), and in periportal and central areas in rat (Steiniger et al., 1984) that capture and process antigens, migrate to lymphoid organs and secrete cytokines to initiate immune responses (Banchereau and Steinman, 1998). The hepatic stellate cells (HSCs) (Blomhoff 1991, Bloom 1994, Sato 2003, Senoo 2004, Senoo 1997, Wake 1971, Wake 1980) that lie in the space between SECs and PCs are considered to be derived from mesenchymal origin. Both ECs and SCs are derived from mesenchymal tissue, namely, septum transversum. Kupffer cells are from monocyte–macrophage system. SCs that store vitamin A in their cytoplasm have been found in extrahepatic organs (kidney, intestine, lung, pancreas, and so on) and characterized (Matano 1999, Nagy 1997, Wake 1980). The purpose of this chapter is to survey recent progress in studies of structure and function of the HSCs (vitamin A‐storing cells).