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Integrated Computational Model of Intracellular Signaling and microRNA Regulation Predicts the Molecular Components and Timing Critical to Hepatic Stellate Cell Activation
Author(s) -
Parrish Austin,
Kuttippurathu Lakshmi,
Vadigepalli Rajanikanth
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.53.4
Subject(s) - hepatic stellate cell , microrna , microbiology and biotechnology , signal transduction , biology , stat3 , cytokine , intracellular , immunology , genetics , gene , endocrinology
Activated hepatic stellate cells (HSCs) play a major role in the development of liver fibrosis. It has been shown that autoregulatory feedback loops between pro‐fibrogenic pathways and microRNAs influence the fate of HSCs. However, the relative contribution of these pathways and regulatory microRNAs to the activation process is unknown. We pursued a computational modeling approach using a Petri net formalism to explore the timing and regulatory balances that are critical to HSC activation. We developed an integrated model incorporating three signaling pathways (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 to activation, whereas NF‐κB and STAT3 alone were unable to induce this switch. Our results show that the relative timing between cytokine stimuli in HSCs alters initial microRNA expression dynamics. Earlier NF‐κB activation resulted in an initial transient increase of both microRNA levels, whereas later activation of NF‐κB versus STAT3 resulted in an initial monotonic decrease in miR‐146a while miR‐21 gradually increased to steady state levels. We observed re‐quiescence from the activated HSC state upon termination of cytokine stimuli. Our model provides a new computational platform for studying HSC activation and the mechanisms where microRNAs act as fine‐tuning markers modulating the system behavior, thereby informing potential therapeutic approaches. Funding: NIAAA R01 AA018873, R21 AA022417, T32 AA007463.