Abstract
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.
Highlights
Hepatic stellate cells (HSC), important for many aspects of liver function in healthy tissue, are primary drivers of liver diseases such as fibrosis and cirrhosis [1,2]
Based on an array of in vitro and in vivo literature, we developed a novel computational model of HSC activation through IL-1β, IL-6, and TGF-β signaling with feedback from miR-21 and miR-146a
Activated stellate cells play a major role in the development of liver fibrosis by contributing to the pro-fibrogenic pathways and other signaling pathways leading to extracellular matrix (ECM) production
Summary
Hepatic stellate cells (HSC), important for many aspects of liver function in healthy tissue, are primary drivers of liver diseases such as fibrosis and cirrhosis [1,2]. During diseases associated with chronic inflammation, HSCs alter their gene and protein expression profiles, change their morphology, and deposit fibrous extracellular matrix (ECM), causing scarring and leading to fibrosis and cirrhosis [1]. The process of HSC activation during chronic inflammation is governed by autocrine and paracrine signaling factors from other non-parenchymal and parenchymal cells and is likely highly dependent on the local microenvironment [2,9]. It is known that the initial changes in HSCs in response to injury could be a result of paracrine stimulation from other non-parenchymal cells.
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