Wendy M. Mars, PhD
Associate Professor of Pathology

Dr. Mars
Dr. Mars is Director of the Cellular and Molecular Pathology Graduate Training Program and a member of the Division of Experimental Pathology.
Office Location:
Rm. S407, S-BST
200 Lothrop Street
Pittsburgh, PA 15261
Contact Information:
Office Telephone: 412-648-9690
Fax: 412-648-1916
Email: wmars@pitt.edu


  • BS - Arizona State University, 1976
  • PhD - University of Texas, 1986

Research Interests

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 interaction 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) is also capable of activating latent HGF to its active form. This specific function of 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, u-PAR and LRP, 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 the exact manner in which u-PA, HGF, and PAI-1 contribute to hepatic regeneration since it remains unclear as to which cell types participate in the growth/regenerative process at what times. As an offshoot of this work we inadvertently discovered that there is an interaction of the u -PA/HGF axis with interleukin-6 (IL-6), a crucial cytokine that regulates the hepatic acute phase response, although the key components of that interaction remain unknown. Hence, the overall focus of the lab is to 1) identify the timing and source of these key regenerative factors (i.e. u-PA, PAI-1, HGF, HGF receptor, IL-6) following hepatic growth/re-growth and 2) clarify the relationship of these proteins within the various cell components of the liver (hepatocytes, stellate cells, endothelia, Kupffer cells). With regard to the first area of focus, we developed a fluorescent in situ hybridization (FISH) technique for detection of cellular mRNA that can be used in conjunction with protein immunofluorescence (IF). By simultaneously utilizing these two techniques, we are now able to definitively demonstrate which cell types produce what mRNAs under varying conditions. A manuscript describing the first of our findings using this technique (that hepatocytes are a previously unidentified source of IL-6 after 70% hepatectomy) has recently been published (Norris et al, PMC3999098). We plan to expand these studies using probes for HGF, the HGF receptor, etc. With regard to the second area of interest, we are presently using the FISH/IF in combination with a genetic approach involving transgenic mice. As Kupffer cells and hepatocytes are two of the most important participants in hepatic regeneration, and as both respond to HGF (Kupffer cells represent an autocrine system, hepatocytes respond in a paracrine manner), we are initially focusing on the contribution of these two cell types using either whole body knockouts or a cre/loxp approach. Cre recombinase under cell-specific promoters (LysZ for macrophages, albumin for hepatocytes) allows us to remove the target genes (HGF or its receptor) from these specific cell populations. For example, genetic loss of the HGF receptor (Coudriet et al, PMC2970559) from bone marrow-derived macrophages leads to altered IL-6 production in response to LPS stimulation. By next removing these genes from the macrophages, or the HGF receptor from hepatocytes, and subsequently subjecting the animals to regenerative stimuli (i.e. hepatectomy, carbon tetrachloride poisoning, ischemia/reperfusion), we will determine the contribution of autocrine versus paracrine HGF-signaling to the regenerative response. Finally, we are also exploring the ability of t-PA to signal through its receptor, LRP1, in stellate cells and hepatocytes. In kidney, we previously found that t-PA pushes a fibrotic response through LRP1. Unexpectedly, we found the opposite to be the case in liver with stellate cells (reversion of activation, manuscript currently under revision). The implication of these findings is that t-PA, an FDA approved drug, may ultimately be of value in treating hepatic fibrosis/cirrhosis; however, due to the potential for inducing kidney fibrosis, a way of specifically targeting treatment to the liver is essential.

NIH Research

View Dr. Mars' NIH RePORT on nih.gov

Selected Publications

View Dr. Mars' publications on PubMed

  1. Norris, C.A., He, M., Kang, L.-I., Ding, M. Q., Radder, J.E., Haynes, M.M., Yang, Y., Paranjpe, S., Bowen, W.C., Orr, A., Michalopoulos, G.K., Stolz, D. B. and Mars, W.M. Synthesis of IL-6 by hepatocytes as a frequent response to common hepatic stimuli. PLoS ONE 9 (4): e96065 (2014) PMID: 24763697, PMCID: PMC3999098.
  2. Koral, K., Paranjpe, S., Bowen, W.C., Mars, W., Luo, J., and Michalopoulos, G.K. Leukocyte-specific protein 1: a novel regulator of hepatocellular proliferation and migration deleted in human hepatocellular carcinoma. Hepatology, 61, 537-547, (2014). PMID: 25234543.
  3. Proto, J.D., Tang, Y., Lu, A., Chen, W.C., Stahl, E., Poddar, M., Beckman, S.A., Robbins, P.D., Nidernhofer, L.J., Imbrogno, K., Hannigan, T., Mars, W.M., Wang, B., and Huard, J. NF-?B inhibition reveals a novel role for HGF during skeletal muscle repair. Cell Death Dis. 6:e1730 (2015) PMID: 25906153.
  4. Kang-L.I., Isse, K., Koral, K., Bowen, W.C., Muratoglu, S.C., Strickland, D.K., Michalopoulos, G.K., Mars, W.M. Tissue-type plasminogen activator suppresses activated hepatic stellate cell activation through low-density lipoprotein receptor-related protein 1. Lab Invest. 10, 1117-1129 (2015) PMID: 26237273 PMC4586397
  5. Paranjpe, S., Bowen, W.C., Mars, W.M., Orr, A., Haynes, M.M., DeFrances, M.C., Liu, S., Tseng, G.C., Tsagianni, A., and Michalopoulos, G.K. Combined systemic elimination of MET and EGFR signaling completely abolishes liver regeneration and leads to liver decompensation. Hepatology 64, 1711-1724 (2016) PMID: 27397846, PMC5074871
  6. Xue, Y., Mars, W.M., Bowen, W., Singhi, A.D., Stoops, J. and Michalopoulous, G.K., Hepatitis C virus (HCV) mimics effects of Glypican 3 (GPC3) on CD81 and promotes development of hepatocellular carcinomas via activation of Hippo pathway in hepatocytes. Am J Pathol. 188, 1469-1477 (2018). PMID 29577937, PMC5975625
  7. Guzman-Lepe, J., Cervantes-Alvarez, E., Collin de l'Hortet, A., Wang, Y, Mars, W.M., Oda, Y., Bekki, Y., Shimokawa, M., Wang, H., Yoshizumi, T., Maehara, Y., Bell, A., Fox, I.J., Takeishi, K & Soto-Gutierrez, A. Liver-Enriched Transcription Factors Expression Relates to Chronic Hepatic Failure in Humans. Hepatology Comm. 2, 582-594 (2018).