Fibroblast mechanotransduction network predicts targets for mechano-adaptive infarct therapies.
Fibroblast mechanotransduction network predicts targets for mechano-adaptive infarct therapies.
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DOI：
10.7554/elife.62856
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发表时间：
2022-02-09
期刊：
影响因子：
7.7
通讯作者：
Richardson WJ
中科院分区：
文献类型：
--
作者：
Rogers JD;Richardson WJ
心肌梗死后纤维化的局部控制对于维持梗死区结构完整性和防止非梗死区胶原积累至关重要。心脏成纤维细胞根据生化和生物力学线索调节基质的更新，但信号通路之间复杂的相互作用使开发局部疤痕形成疗法的努力变得混乱。我们采用基于逻辑的成纤维细胞机械-化学信号转导常微分方程模型来预测典型生化刺激和机械张力下基质蛋白的表达。机械-化学相互作用的功能分析显示，对生化刺激的张力放大、抑制或逆转反应具有广泛的通路串扰。综合药物靶标筛选确定了13种机械适应性疗法，这些疗法可以促进需要区域的基质积累，并降低不需要区域的基质水平。我们的预测表明，机械-化学相互作用可能介导许多组织的细胞行为，并证明了多途径信号网络在发现针对环境特异性疾病状态的治疗方法中的实用性。
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 confound efforts to develop therapies for regional scar formation. 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 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 suggest that mechano-chemo interactions likely mediate cell behavior across many tissues and demonstrate the utility of multi-pathway signaling networks in discovering therapies for context-specific disease states.