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

Murine models of hepatic injury have recently come to the forefront in hepatic progenitor cell research, including investigations of so-called ‘plasticity phenomena’, i.e. engraftment of circulating, sometimes marrow-derived cells as hepatocytes, cholangiocytes and oval cells. In this developing field, there have been many reports presenting seemingly contradictory data that have added to confusion. Some of these contradictions may involve differences in donor cells (whole bone marrow vs. haematopoietic stem cells vs. mesenchymal stem cells), strain, age and gender differences of animal subjects, detection technique and injury (1–19). Different models of injury have been used in many different studies and these different models may represent very different phenomena, that call forth different physiological responses to the injuries (20). Commonly reported hepatic injuries have included damage related to marrow-lethal radiation in the preparation of marrow-transplanted animals (2), the fumaryl acetoacetate hydroxylase (FAH)-null mouse (11), a model of type I human tyrosinaemia and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) biliary toxicity (4, 21). It is now known that engraftment phenomena may occur by at least two pathways: by fusion of circulating cells with pre-existing hepatobiliary cells and by direct differentiation of engrafting cells (6, 12, 13, 22, 23). The FAH-null mouse exemplifies the fusion pathway. Radiation-related injury may involve both processes (24). The DDC model of injury has been used to generate abundant oval cells, which appear to be of bone marrow origin in some reports but not in others (4, 22, 25). When fusion is the underlying mechanism, it is probable that cells of the monocyte/macrophage lineage enter the liver and fuse directly with pre-existing hepatocytes (26). There is no apparent site specificity for this process and chemokine/cytokine influences on it have not yet been reported. On the other hand, engraftment by direct differentiation may occur by direct engraftment in the terminal branches of the biliary tree, the putative site of a hepatic progenitor cell niche, perhaps first differentiating into oval cells, before maturing into hepatocytes and/or cholangiocytes (5, 27). Factors that may influence this process include stromal-derived factor-1 (SDF-1) (28) and the c-kit ligand, stem cell factor (SCF) (29–34). SDF-1 is upregulated in proliferating oval cells and recruits marrow-derived CD34+ cells to the site of injury (28). Exogenous delivery of SDF-1 by an adenoviral vector results in increased mobilization of haematopoietic stem and progenitor cells from the marrow compartment to blood in immunodeficient mice (35). SCF and SDF-1 act synergistically to increase the chemotaxis of CD34+ cells in vitro, suggesting that both play a role in the recruitment of stem cells to injured liver (28). In the 2-acetylaminofluorene (2-AAF)/partial hepatectomy model of oval cell induction, c-kit mRNA is upregulated in oval cells, while SCF transcripts are upregulated in both oval cells and stellate cells (31). SCF is also upregulated by hepatic stellate cells during myofibroblastic activation (32), perhaps contributing to fibrosis in chronic liver injury. Expression of c-kit, the SCF receptor, is markedly increased in paediatric human bile duct (BD) cells in the setting of fulminant hepatic failure, suggesting a role of SCF and c-kit in liver repair (34). Mice deficient in c-kit have impaired oval cell proliferation in response to BD ligation (30) and 2-AAF/partial hepatectomy (36). Exogenous administration of SCF coincident with acetaminophen dramatically reduced lethality and reduced histological liver injury in mice, while neutralizing antibodies against SCF increased both lethality and histological injury (33). It is not clear what role SCF plays, if any, in liver repair in injuries where oval cell proliferation is not a prominent feature. Here we compare three types of liver injury to emphasize the importance of these differences in evaluating the role of stem and progenitor cells in tissue repair after liver injury. We use a well-established technique to quantify oval cell reactions (37), and evaluate SCF and SDF-1 in tissue (by immunofluorescence) and in serum (by ELISA). The observed differences may influence the comparison of data derived from experiments involving the different models. Understanding these differences may lead to greater clarity of interpretation of reported data and more precise experimental design for future experiments.