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Activation and deactivation of hepatic stellate cells (HSCs) is an important mechanism contributing to both healthy liver function and development of liver diseases, which relies on the interplay between numerous signaling pathways. There is accumulating evidence for the regulatory role of microRNAs that are downstream from these pathways in HSC activation. However, the relative contribution of these pathways and interacting microRNA regulators to the activation process is unknown. We pursued a computational modeling approach to explore the timing and regulatory balances that are critical to HSC activation and quiescence. We developed an integrated model incorporating three signaling pathways with crosstalk (NF-κB, STAT3 and TGF-β) and two microRNAs (miR-146a,  miR-21) that are differentially regulated by these pathways. Simulations demonstrated that TGF-β-mediated regulation of microRNAs is critical to drive the HSC phenotypic switch from quiescence (miR-146ahigh miR-21low) to an activated state (miR-146alow miR-21high). We found that the relative timing between peak NF-κB and STAT3 activation plays a key role driving the initial dynamics of miR-146a. We observed re-quiescence from the activated HSC state upon termination of cytokine stimuli. Our integrated model of signaling and microRNA regulation provides a new computational platform for investigating  the mechanisms driving HSC molecular state phenotypes in normal and pathological  liver physiology

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Integrated Computational Model of Intracellular Signaling and microRNA Regulation Predicts the Network Balances and Timing Constraints Critical to the Hepatic Stellate Cell Activation Process