A computational model of cardiac fibroblast signaling predicts context-dependent drivers of myofibroblast differentiation
| Autor: | Jeffrey J. Saucerman, Jeffrey W. Holmes, William J. Richardson, Angela C. Zeigler |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cell signaling Cardiac fibrosis Systems biology Context (language use) Biology Models Biological Article 03 medical and health sciences Transforming Growth Factor beta Fibrosis medicine Animals Humans Computer Simulation Myofibroblasts Fibroblast Molecular Biology Cells Cultured Gene Expression Profiling Computational Biology Cell Differentiation medicine.disease Cell biology 030104 developmental biology medicine.anatomical_structure Signal transduction Cardiology and Cardiovascular Medicine Myofibroblast Signal Transduction |
| Zdroj: | Journal of Molecular and Cellular Cardiology. 94:72-81 |
| ISSN: | 0022-2828 |
| DOI: | 10.1016/j.yjmcc.2016.03.008 |
| Popis: | Cardiac fibroblasts support heart function, and aberrant fibroblast signaling can lead to fibrosis and cardiac dysfunction. Yet how signaling molecules drive myofibroblast differentiation and fibrosis in the complex signaling environment of cardiac injury remains unclear. We developed a large-scale computational model of cardiac fibroblast signaling in order to identify regulators of fibrosis under diverse signaling contexts. The model network integrates 10 signaling pathways, including 91 nodes and 134 reactions, and it correctly predicted 80% of independent previous experiments. The model predicted key fibrotic signaling regulators (e.g. reactive oxygen species, tissue growth factor β (TGFβ) receptor), whose function varied depending on the extracellular environment. We characterized how network structure relates to function, identified functional modules, and predicted cross-talk between TGFβ and mechanical signaling, which was validated experimentally in adult cardiac fibroblasts. This study provides a systems framework for predicting key regulators of fibroblast signaling across diverse signaling contexts. |
| Databáze: | OpenAIRE |
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