Fibroblast Mechanotransduction Network Predicts Targets for Mechano-Adaptive Infarct Therapies

Abstract

Regional control of fibrosis after myocardial infarction is critical for maintaining structural integrity in the infarct while preventing collagen accumulation in non-infarcted areas. Cardiac fibroblasts modulate matrix turnover in response to biochemical and biomechanical cues, but the complex interactions between signaling pathways confounds efforts to develop therapies for regional scar formation. Here, we employed a logic-based ordinary differential equation model of fibroblast mechano-chemo signal transduction to predict matrix protein expression in response to canonical biochemical stimuli and mechanical tension. Functional analysis of mechano-chemo interactions showed extensive pathway crosstalk with tension amplifying, dampening, or reversing responses to biochemical stimuli. Comprehensive drug target screens in low- and high-tension contexts identified 13 mechano-adaptive therapies that promote matrix accumulation in regions where it is needed and reduce matrix levels in regions where it is not needed. Our predictions demonstrate this approach's utility for discovering context-specific mechanisms mediating fibrosis and druggable targets for spatially resolved therapies.

Network modeling predicts personalized gene expression and drug responses in valve myofibroblasts cultured with patient sera

“…Upon filtering the initial gene regulatory network for interactions contained in either database, the resulting network was filtered further for interactions containing TFs or fibrosis-related target genes in myofibroblasts. Lists of TFs and target genes were derived using our curated network model of myofibroblast signaling ( 59 ), which contains 11 primary TFs and 20 target genes coding for ECM-related proteins. For TFs that consist of several subunits (e.g., activator protein 1 [AP1] complex), both constituent genes were included for filtering.…”

“…We combined the final transcriptional network with our previous myofibroblast signaling network describing intracellular mechanotransduction and chemotransduction ( 59 ) to form a composite network capable of predicting fibrosis-related protein expression in response to mechanical and biochemical stimuli. New TFs (model nodes) and/or transcriptional reactions (edges) were added to the cell signaling topology if they were not redundant to the original transcriptional reactions described by the signaling network.…”

Mitral Valve Prolapse Induces Regionalized Myocardial Fibrosis

“…To help identify potential signaling connections between mechanical tension and regional fibrosis, we adapted a previously published computational model of cardiac fibroblast (CF) signaling pathways. 21 , 22 This model captured the activity levels of 109 signaling molecules and 174 reactions connecting biochemical and mechanical input stimuli (mechanical tension, transforming growth factor beta 1, angiotensin II, interleuken 1, interleuken 6, platelet‐derived growth factor, tumor necrosis factor alpha, endothelin 1, norepinephrine, and natriuretic peptide) to predict fibrosis‐related outputs (collagen I, collagen III, fibronectin, periostin, α‐SMA, matrix metalloproteinases, tissue inhibitors of metalloproteinases, and others). In the present study, we integrated an additional 27 new signaling molecules and 50 new network reactions related to cilia signaling that were manually curated from existing literature reports (Tables S2 and S3 ).…”

“… 22 In our past modeling studies, this model has successfully predicted ≈82% (96/118) of previously reported signaling responses by CFs under a wide variety of biomechanical and biochemical stimulation conditions. 21 , 22 Importantly, these validation agreements are based on >100 independent experimental studies, not including the ≈300 experimental studies used to build the model. In the current study, we investigated the connection between mechanical tension, cilia signaling, and downstream collagen production.…”

Effects of Sex and 17β-Estradiol on Cardiac Fibroblast Morphology and Signaling Activities <em>in vitro</em>

“…One way to hasten this investigation could be through the use of sex-specific computational disease models. Existing disease models such as the signaling network model of cardiac fibroblasts' response to mechano-chemo signaling could be improved through the incorporation of biological sex and hormone pathways [37,38]. Large-scale sex-specific network modeling could greatly accelerate the pace and reduce the costs of identifying important interactions involved in the regulation of fibrosis rather than trial and error experiments alone.…”