Association of growth factors (GFs) with extracellular matrix (ECM) proteins occurring in vivo is thought to enhance duration and potency of GF signaling. The contributions of ECM are not reflected in traditional in vitro experiments where GFs are added in soluble form into the cell culture media. The high cost of GFs also confounds experiments such as stem cell cultivation where large amounts of these reagents are required. It is known that freshly isolated hepatocytes cultured in vitro dedifferentiate rapidly, losing liver function. It has been shown that albumin secretion, urea synthesis and cytochrome P450 enzymatic activity dramatically decrease within days of culture. The work reported in this dissertation was aimed at developing GF microarrays, cultivating hepatocytes on top of GFs and screening the effects of GFs on hepatic phenotype during in vitro liver injury. We discovered that hepatocytes cultured on top of hepatocyte growth factor (HGF) and bone morphogenetic protein (BMP) 7 were protected against apoptosis and fibrosis during alcohol exposure in a GF concentration dependent fashion. In contrast, hepatocytes cultured on transforming growth factor (TGF) β were driven to apoptosis. In another set of experiments, we used GF arrays to control epithelial versus mesenchymal phenotype of hepatocytes in the same petri dish solely based on the types of growth factors imprinted on the surface. In the future, the GF microarray will be used for screening inducers of liver phenotype in embryonic stem cells. We also envision the GF microarray platform as a tool for developing GF-based anti-fibrotic therapies.
|Commitee:||Reddi, A. H., Yamada, Soichiro|
|School:||University of California, Davis|
|School Location:||United States -- California|
|Source:||DAI-B 71/11, Dissertation Abstracts International|
|Keywords:||Cell differentiation, Growth factor microarrays, Hepatocyte growth factor, Hepatocytes, Liver injury, Micropatterned cocultures, Protein microarrays|
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