Molecular basis for calcium signaling in hepatic stellate cells

Progressive liver fibrosis ( with the resultant cirrhosis) is the primary cause of chronic liver failure. Hepatic stellate cells ( HSCs) are critically important mediators of liver fibrosis. In the healthy liver, HSCs are quiescent lipid-storing cells limited to the perisinusoidal endothelium. However, in the injured liver, HSCs undergo myofibroblastic transdifferentiation ( activation), which is a critical step in the development of organ fibrosis. HSCs express P2Y receptors linking extracellular ATP to inositol ( 1,4,5)trisphosphate- mediated cytosolic Ca2+ signals. Here, we report that HSCs express only the type I inositol ( 1,4,5)- trisphosphate receptor and that the receptor shifts into the nucleus and cell extensions upon activation. These cell extensions, furthermore, express sufficient machinery to enable local application of ATP to evoke highly localized Ca2+ signals that induce localized contractions. These autonomous units of subcellular signaling and response reveal a new level of subcellular organization, which, in turn, establishes a novel paradigm for the local control of fibrogenesis in the liver.