Dissecting the influences of combinatorial microenvironments on hepatic stellate cell phenotype and behavior

Statement of Purpose: Non-alcoholic steatohepatitis (NASH) is an emerging epidemic of liver disease and the basis for a rising incidence of fibrosis and hepatocellular carcinoma ¹ . Recently, hepatic stellate cells (HSCs) have been identified as the primary drivers of liver fibrosis ² . Changes in the composition of the liver microenvironment during fibrosis results in a complex crosstalk of extracellular cues that promotes the activation, or differentiation, of HSCs from a quiescent, vitamin A storing phenotype to a myofibroblastic phenotype. While these chemo-mechanical signaling processes are well understood in rodent HSC models, very little is known about extracellular influences on HSC activation in humans. Here, we have utilized a high-throughput cellular microarray platform to dissect the cooperative influences of defined combinations of extracellular matrix (ECM) proteins and substrate stiffnesses on human HSC phenotype and behavior ³ .