Abstract

Growth of human hepatocytes in response to regenerative stimuli or in neoplastic conditions is a phenomenon manifested in all forms of human hepatic disease. Loss of hepatic parenchyma due to any toxins or chemical carcinogens or inflammatory conditions results in regenerative response aimed to restore the organ mass. In hepatic neoplasms (hepatocellular carcinoma, adenoma). abnormal growth is the hallmark of the neoplastic phenotype. Very recently, we have been able to purify and characterize the human Hepatopoietin A and the human Hepatopoietin B. These substances stimulate hepatocyte proliferation in serum free cultures. In addition, we found that ECGF stimulates proliferation of a subset of rat hepatocytes and is a strong mitogen for human hepatocytes. We have also adapted the 2% DMSO protocol and succeeded in setting up a cyclic system in which DNA synthesis can be turned off and on. This allows multiple periods of DNA synthesis in hepatocytes in culture (with multiple cell cycles per period). Human hepatocytes, in contrast to rat hepatocytes, respond poorly to EGF, respond stronger to ECGF and maintain better differentiation in culture. This proposal aims to characterize the response of normal and neplastic human hepatocytes to these growth factors and growth inhibitors such as TGFbeta and IL-6. Expression of the growth factors and their receptors by human hepatocytes will also be examined in human liver needle biopsies. These studies will be extended to cover the behavior of human hepatocytes transplanted in ECGF- impregnated endothelialized collagen sponges. The effect of chemical carcinogen initiators and tumor promoters will also be examined in this transplantation system.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA030241-14
Application #
3169137
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1981-08-15
Project End
1994-07-31
Budget Start
1993-06-01
Budget End
1994-07-31
Support Year
14
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213

  Publications

Kang, Liang-I; Isse, Kumiko; Koral, Kelly et al. (2015) Tissue-type plasminogen activator suppresses activated stellate cells through low-density lipoprotein receptor-related protein 1. Lab Invest 95:1117-29
Lin, Chih-Wen; Mars, Wendy M; Paranjpe, Shirish et al. (2011) Hepatocyte proliferation and hepatomegaly induced by phenobarbital and 1,4-bis [2-(3,5-dichloropyridyloxy)] benzene is suppressed in hepatocyte-targeted glypican 3 transgenic mice. Hepatology 54:620-30
Liu, Bowen; Bell, Aaron W; Paranjpe, Shirish et al. (2010) Suppression of liver regeneration and hepatocyte proliferation in hepatocyte-targeted glypican 3 transgenic mice. Hepatology 52:1060-7
Liu, Bowen; Paranjpe, Shirish; Bowen, William C et al. (2009) Investigation of the role of glypican 3 in liver regeneration and hepatocyte proliferation. Am J Pathol 175:717-24
Gkretsi, Vasiliki; Apte, Udayan; Mars, Wendy M et al. (2008) Liver-specific ablation of integrin-linked kinase in mice results in abnormal histology, enhanced cell proliferation, and hepatomegaly. Hepatology 48:1932-41
Limaye, Pallavi B; Alarcon, Gabriela; Walls, Andrew L et al. (2008) Expression of specific hepatocyte and cholangiocyte transcription factors in human liver disease and embryonic development. Lab Invest 88:865-72
Limaye, Pallavi B; Bowen, William C; Orr, Anne V et al. (2008) Mechanisms of hepatocyte growth factor-mediated and epidermal growth factor-mediated signaling in transdifferentiation of rat hepatocytes to biliary epithelium. Hepatology 47:1702-13
Gkretsi, Vasiliki; Bowen, William C; Yang, Yu et al. (2007) Integrin-linked kinase is involved in matrix-induced hepatocyte differentiation. Biochem Biophys Res Commun 353:638-43
Gkretsi, Vasiliki; Mars, Wendy M; Bowen, William C et al. (2007) Loss of integrin linked kinase from mouse hepatocytes in vitro and in vivo results in apoptosis and hepatitis. Hepatology 45:1025-34
Luo, Jian-Hua; Ren, Baoguo; Keryanov, Sergei et al. (2006) Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas. Hepatology 44:1012-24

Showing the most recent 10 out of 104 publications