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

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-146a high miR-21 low) to an activated state (miR-146a low miR-21 high). 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

A novel comparative pattern analysis approach identifies chronic alcohol mediated dysregulation of transcriptomic dynamics during liver regeneration

“…We hypothesize that these HSC-specific gene activations, by altering the push-pull balance between pro-regenerative phenotype and that of an anti-regenerative molecular state, helps to fine-tune the proliferation-inhibitory response associated with ethanol adaptation. Utilization of computational modeling [ 93 – 95 ] can further help characterize and understand how dynamic alterations in microenvironment and HSC activation within the liver contribute to deficient liver regeneration.…”

Systems analysis of non-parenchymal cell modulation of liver repair across multiple regeneration modes

“…To facilitate this integration, one could consider the existing models of macrophage or Kupffer cell activation and hepatic stellate cell activation. For instance, macrophage activation has been studied using a computational model of the cytokine-mediated pathways [ 39 , 40 ]. Specific to the liver, our group has recently developed a computational model of cytokine-mediated hepatic stellate cell activation that incorporates multiple pathways with cross-talk as well as microRNA mediated regulation [ 39 , 40 ].…”

Dysregulation of miR-21-associated miRNA regulatory networks by chronic ethanol consumption impairs liver regeneration

“…Gene ontology analysis of putative miRNA targets reveals several critical functions, including regulation of cell death, differentiation, and development, may be shifted by differential miRNA expression (Table 1). In particular, changes in the TGF-b signaling pathway have been widely studied in the context of liver injury and repair, and seem to be directly regulated by several miRNAs, including miR-21 and miR-146a (26).…”

“…miR-146a, which was most anticorrelated with miR-21 expression (Fig. 3C), is reported to act as a tumor suppressor and is involved in the regulation of hepatic stellate cell activity, suggesting a possible functional role of this miRNA in controlling gene expression in the context of response to partial hepatectomy following miR-21 inhibition (21,(25)(26)(27).…”