The fibroblast is a key mediator of wound healing in the heart and other organs, yet how it integrates multiple time-dependent paracrine signals to control extracellular matrix synthesis has been difficult to study in vivo. Here, we extended a computational model to simulate the dynamics of fibroblast signaling and fibrosis after myocardial infarction (MI) in response to time-dependent data for nine paracrine stimuli. This computational model was validated against dynamic collagen expression and collagen area fraction data from post-infarction rat hearts. The model predicted that while many features of the fibroblast phenotype at inflammatory or maturation phases of healing could be recapitulated by single static paracrine stimuli (interleukin-1 and angiotensin-II, respectively), mimicking the reparative phase required paired stimuli (e.g. TGFβ and endothelin-1). Virtual overexpression screens simulated with either static cytokine pairs or post-MI paracrine dynamic predicted phase-specific regulators of collagen expression. Several regulators increased (Smad3) or decreased (Smad7, protein kinase G) collagen expression specifically in the reparative phase. NADPH oxidase (NOX) overexpression sustained collagen expression from reparative to maturation phases, driven by TGFβ and endothelin positive feedback loops. Interleukin-1 overexpression had mixed effects, both enhancing collagen via the TGFβ positive feedback loop and suppressing collagen via NFκB and BAMBI (BMP and activin membrane-bound inhibitor) incoherent feed-forward loops. These model-based predictions reveal network mechanisms by which the dynamics of paracrine stimuli and interacting signaling pathways drive the progression of fibroblast phenotypes and fibrosis after myocardial infarction.

成纤维细胞是心脏和其他器官伤口愈合的关键介质，但它如何整合多个时间依赖性旁分泌信号来控制细胞外基质合成一直很难在体内研究。在这里，我们扩展了一个计算模型来模拟心肌梗死（MI）后成纤维细胞信号传导和纤维化的动态，以响应九种旁分泌刺激的时间依赖性数据。该计算模型针对梗塞后大鼠心脏的动态胶原蛋白表达和胶原蛋白面积分数数据进行了验证。该模型预测，虽然成纤维细胞表型在炎症或愈合成熟阶段的许多特征可以通过单一静态旁分泌刺激（分别是白细胞介素-1和血管紧张素-II）来重现，但模拟修复阶段所需的配对刺激（例如TGFβ和内皮素） -1）。使用静态细胞因子对或心肌梗死后旁分泌动态预测的胶原蛋白表达的阶段特异性调节剂模拟虚拟过表达筛选。一些调节因子会增加（Smad3）或减少（Smad7，蛋白激酶 G）胶原蛋白表达，特别是在修复阶段。NADPH 氧化酶 (NOX) 过度表达在 TGFβ 和内皮素正反馈环的驱动下，维持胶原蛋白从修复期到成熟期的表达。Interleukin-1 过度表达具有混合效应，既通过 TGFβ 正反馈环路增强胶原蛋白，又通过 NFκB 和 BAMBI（BMP 和激活素膜结合抑制剂）不相干前馈环路抑制胶原蛋白。这些基于模型的预测揭示了旁分泌刺激的动态和相互作用的信号通路驱动心肌梗死后成纤维细胞表型和纤维化进展的网络机制。