Probing Combinatorial Hepatocellular Microenvironments

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DESCRIPTION (provided by applicant): Stability of liver-specific functions in hepatocytes is critical to the success of hepatocyte-based therapies for liver disease. The influences of microenvironmental factors such as soluble stimuli, extracellular matrix (ECM), and interactions with neighboring cells are thought to be important in regulation of the hepatocyte phenotype. Because it has historically been difficult to modulate these micro-environmental cues independently from each other, it remains unclear how they cooperate to exert their influence on hepatocellular function. To systematically investigate the interaction of micro-environmental cues, a novel platform is proposed that exploits robotic spotting technology to culture hepatocytes atop ECM microdomains within combinatorial microfluidic environments. In specific aim 1, the platform will be designed and characterized. Jn specific aim 2, the platform will be used to probe hepatocellular responses to combinations of HGF, EOF, and TGFalpha while plated upon laminin, collagen I, and fibronectin. A clear picture of the interplay between soluble and insoluble cues will be fundamental to the future design and implementation of hepatocyte-based therapies to treat liver disease.