This competing renewal application proposes to continue studies dissecting the regulatory role of the plasminogen (Plg) on liver repair. During the first tenure of the award, we used a series of unique mouse models to demonstrate that Plg plays an essential regulatory role in liver repair by controlling the proteolytic removal of necrotic liver cells and the reorganization of the lobular architecture. Although we found no evidence that Plg activators independently control liver repair, we demonstrated that they work in synergism to modulate liver repair by controlling the proteolytic activation of Plg into the active protease plasmin. Recent exploratory studies to dissect the molecular and cellular mechanisms used by Plg to regulate liver repair, we found preliminary evidence that Plg is required for the proteolytic processing of circulating HGF and for the maintenance of the differentiated phenotype in fully mature livers. During liver repair, plasminogen deficiency triggered the emergence of liver cells displaying a genetic program present in early progenitor cells. In the present application, we propose an overall goal of dissecting the molecular mechanisms used by Plg to regulate liver repair and cellular plasticity. This goal will be accomplished by two complementary aims. In the first aim, we will determine the molecular targets of plasminogen during liver repair by investigating the mechanisms used by Plg to induce HGF-Met signaling and to control hepatocyte motility, and by dissecting the intracellular events that orchestrate the cellular response of hepatocytes to an injury. In the second aim, we will establish the role of plasminogen in the control of liver cell plasticity by: 1) fully defining the phenotype and developmental properties of undifferentiated liver cells that emerge in livers of plasminogen-deficient mice, 2) how extracellular fibrin dictates a transcriptional re-programming to an embryonic stage, and 3) investigating the lineage of undifferentiated cells in relation to cells from within the hepatic environment or from the bone marrow. Collectively, the proposed work will provide novel insight into how plasminogen interacts with extracellular factors to orchestrate the reparative response of the liver to an injury, and how the immediate pericellular environment fosters the emergence of liver cells with progenitor properties. These studies are relevant to human health by the identification of potential therapeutic targets to restore liver function in patients and by advancing the current understanding of liver stem cell biology. ? ? ? ? ?
|Shanmukhappa, Kumar; Matte, Ursula; Degen, Jay L et al. (2009) Plasmin-mediated proteolysis is required for hepatocyte growth factor activation during liver repair. J Biol Chem 284:12917-23|
|Shanmukhappa, Kumar; Sabla, Gregg E; Degen, Jay L et al. (2006) Urokinase-type plasminogen activator supports liver repair independent of its cellular receptor. BMC Gastroenterol 6:40|
|Shanmukhappa, Kumar; Mourya, Reena; Sabla, Gregg E et al. (2005) Hepatic to pancreatic switch defines a role for hemostatic factors in cellular plasticity in mice. Proc Natl Acad Sci U S A 102:10182-7|
|Currier, Angela R; Sabla, Gregg; Locaputo, Stephanie et al. (2003) Plasminogen directs the pleiotropic effects of uPA in liver injury and repair. Am J Physiol Gastrointest Liver Physiol 284:G508-15|
|Ng, V L; Sabla, G E; Melin-Aldana, H et al. (2001) Plasminogen deficiency results in poor clearance of non-fibrin matrix and persistent activation of hepatic stellate cells after an acute injury. J Hepatol 35:781-9|
|Pohl, J F; Melin-Aldana, H; Sabla, G et al. (2001) Plasminogen deficiency leads to impaired lobular reorganization and matrix accumulation after chronic liver injury. Am J Pathol 159:2179-86|
|Bezerra, J A; Currier, A R; Melin-Aldana, H et al. (2001) Plasminogen activators direct reorganization of the liver lobule after acute injury. Am J Pathol 158:921-9|