Wendy M. Mars, PhD

Historically, the main focus of my research has been to understand the roles of the urokinase- and tissue-type plasminogen activators (u-PA and t-PA) in tissue regeneration, particularly with regard to their interactions with their stoichiometric target, Hepatocyte Growth Factor (HGF). Although u-PA and t-PA are best known for their enzymatic roles in fibrinolysis and cancer metastases, in the early 90's we, and others, demonstrated that u-PA and t-PA are also capable of activating latent HGF to its active form, suggesting non-canonical roles for these two proteins. Stoichiometric activation of HGF by u-PA is of particular importance during hepatic generation/regeneration, where HGF serves as an essential molecule for liver growth. HGF and u-PA, as well as the u-PA inhibitor (PAI-1), as well as their receptors MET (for HGF), u-PAR (for u-PA) and LRP1 (for u-PA and/or t-PA), are either made or utilized by multiple hepatic cell types including hepatocytes, Kupffer cells (hepatic macrophages), stellate cells and sinusoidal endothelia. This poses a problem in fully understanding exactly how u-PA, HGF, and PAI-1 contribute to hepatic regeneration since it is difficult to discern which cell types participate in the growth/regenerative process at what times. In order to explore this area of research more fully, we initially developed a fluorescent in situ hybridization (FISH) technique for detection of cellular mRNAs that can be used in conjunction with protein immunofluorescence (IF). By simultaneously utilizing FISH and IF, we are able to definitively demonstrate which cell types produce particular mRNAs and proteins at any particular time (PMC3999098).

Interesting, as an offshoot of this study, we inadvertently discovered that the u-PA/HGF axis interacts with interleukin-6 (IL-6), a crucial cytokine controlling hepatic survival that also regulates the hepatic acute phase response. Hence, we additionally began investigating novel interactions these proteins (u-PA, u-PAR, HGF, PAI-1, MET, t-PA, LRP1) have with other pathways known to be important in hepatic homeostasis. Using a cell-specific targeted cre/loxp approach (LysZ for macrophages, albumin for hepatocytes, tamoxifen for all cell types) we demonstrated that constitutive activation of MET in bone marrow-derived macrophages leads to suppressed IL-6 production in response to LPS stimulation (PMC2970559) whereas, in hepatocytes HGF acts as a direct stimulus for IL-6 production (PMC3999098).

In other investigations we have also been able to show that t-PA-mediated signaling through LRP1 in stellate cells reverses their activation (PMC4586397) whereas in kidney, t-PA actually pushes a fibrotic response through the same receptor. The implication of these latter findings is that t-PA, an FDA approved drug, may ultimately be of value in hepatic fibrosis/cirrhosis; however, due to the potential for inducing kidney fibrosis, a way of specifically targeting treatment to the liver will be essential. Finally, we recently discovered that LRP1 can act as a transcriptional regulator of lipid metabolism in hepatocytes. Those studies have implications for steatosis, type 2 diabetes, and cirrhosis and are currently ongoing.