Hepatic oval (stem) cell expression of endothelial differentiation gene receptors for lysophosphatidic acid in mouse chronic liver injury

Abstract

Growth factor lysophosphatidic acid (LPA) regulates cell proliferation and differentiation and increases motility and survival in several cell types, mostly via G-protein-coupled receptors encoded by endothelial differentiation genes (EDG). We show herein that hepatic oval (stem) cell proliferation, induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) in a mouse model of chronic liver injury, was associated with the expression of LPA1, LPA2, and LPA3 receptor subtypes; only LPA1 receptor protein was detectable in normal liver by western blot. In the injured liver, enhanced LPA1 receptor was identified predominantly in oval cells along the portal tract, proliferating ductular epithelial cells, and small cells, which were located in the nearby parenchyma and formed clusters. Interestingly, the LPA1 receptor was co-expressed in DDC-treated livers with the stem cell antigen SCA-1, suggesting that this receptor may be associated with bone marrow-derived progenitors. All three receptors for LPA were detected mostly in small cells in the vicinity of the portal tract, and co-localized with the A6 antigen, a marker of ductular oval cells. In addition, hepatic levels of endogenous LPA were significantly higher in DDC-fed mice compared to normal animals. We propose that the expression of diverse LPA receptors may be a necessary part of the mechanism responsible for activation of oval cells during liver injury. As a result, LPA and its analogs may represent critical endogenous mediators, which regulate survival, increase motility, and modulate proliferation and differentiation of hepatocyte progenitors in regenerating liver.