Physiological variations of stem cell factor and stromal‐derived factor‐1 in murine models of liver injury and regeneration

Abstract

Stem cell factor (SCF) and stromal-derived factor-1 (SDF-1) regulate the regenerative response to liver injury, possibly through activation of liver progenitor 'oval' cells and recruitment of circulating, marrow-derived progenitors. We performed a detailed analysis of SCF, SDF-1 and oval cell proliferation induced by tyrosinaemia, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or liver irradiation in mice by ELISA and immunofluorescence. Liver injury in the tyrosinaemia mouse is characterized by a dramatic decline in plasma SCF and absence of oval cell proliferation. In contrast, DDC induces bile duct (BD) and oval cell proliferation, and a modest decline in plasma SCF. Focal liver irradiation increases plasma SCF, but not oval cell density. In normal mouse liver, SCF is localized primarily to Kupffer cells, cholangiocytes and arterial smooth muscle, with little or no expression in hepatocytes. However, SCF appears in hepatocyte nuclei after injury, where its function is unknown. In all three models, SDF-1 is expressed exclusively in BD epithelium, indicating that tissue SDF-1 levels are proportional to the total mass of oval cells and cholangiocytes. However, increased plasma levels of SDF-1 in fumaryl acetoacetate hydroxylase-null mice were not accompanied by oval cell proliferation. Changes in SCF and SDF-1 varied with the nature of liver injury and were not directly related to oval cell proliferation.