| Chronic liver disease is increasing in prevalence worldwide; however, few medical therapies are available to treat liver cirrhosis and failure. Hepatic stellate cell (HSC) activation and trans-differentiation into myofibroblast-like (MFB-like) cells is a key process in liver injury and fibrogenesis. Greater understanding of the role of matrix regulating proteases, such as the plasminogen activators, in HSC activation could provide new therapeutic targets for treating chronic liver disease. Mice lacking plasminogen activators exhibit delay in liver repair; however, their exact functions after liver injury remain unclear. Recent studies in kidney demonstrate that low density lipoprotein receptor-related protein 1 (LRP1)-dependent signaling by tissue-type plasminogen activator (t-PA) is an essential regulator of the myofibroblast phenotype after injury. This study investigated the role of t-PA and LRP1 in HSC activation and in vivo liver injury. We find that, in contrast to kidney fibroblasts, exogenous t-PA antagonizes activation of primary and immortalized HSCs in vitro. Similar to kidney, these effects are independent of the proteolytic function of t-PA and require phosphorylation of LRP1. Antagonism of LRP1 or PI3K/Akt signaling pathways is able to prevent t-PA-mediated decreases in α-SMA. During recovery following acute liver injury, mice lacking t-PA (globally) or LRP1 (conditionally on HSCs) retain higher densities of the α-SMA+ MFB-like cell population compared to control mice. These differences are seen at time points that correspond to the appearance of co-localization between p-LRP1 and α-SMA, as well as t-PA immunolocalization at sites of α-SMA-positive cells. Additionally, t-PA may regulate macrophage phenotype and drug metabolism, as t-PA null mice exhibit increased macrophage accumulation and lack of normal compensatory down-regulation of a key metabolic enzyme after acute injury. Finally, more collagen I deposition remains in the livers of t-PA null mice up to two weeks after cessation of chronic liver injury, suggesting a decreased rate of matrix turnover. These data reveal that t-PA has multiple functions in liver repair and is able to affect the phenotype of several cell types, in addition to its classical plasminogen activating role. Further preclinical studies are needed to evaluate the clinical potential of using t-PA as a treatment for chronic liver injury and fibrosis. |
