Tissue repair is a protective response after injury, but repetitive or prolonged injury can lead to fibrosis, a pathological state of excessive scarring. To pinpoint the dynamic mechanisms underlying fibrosis, it is important to understand the principles of the cell circuits that carry out tissue repair. In this study, we establish a cell-circuit framework for the myofibroblast-macrophage circuit in wound healing, including the accumulation of scar-forming extracellular matrix. We find that fibrosis results from multistability between three outcomes, which we term “hot fibrosis” characterized by many macrophages, “cold fibrosis” lacking macrophages, and normal wound healing. This framework clarifies several unexplained phenomena including the paradoxical effect of macrophage depletion, the limited time-window in which removing inflammation leads to healing, and why scar maturation takes months. We define key parameters that control the transition from healing to fibrosis, which may serve as potential targets for therapeutic reduction of fibrosis.

组织修复是损伤后的一种保护性反应，但是重复性或长期性损伤可导致纤维化，这是过度瘢痕形成的病理状态。为了查明纤维化的潜在动力学机制，重要的是了解进行组织修复的细胞回路的原理。在这项研究中，我们为伤口愈合中的成纤维细胞-巨噬细胞回路建立了细胞回路框架，包括形成疤痕的细胞外基质的积累。我们发现纤维化是由三个结局之间的多重稳定性导致的，我们将其称为“热纤维化”，其​​特征是许多巨噬细胞，缺乏巨噬细胞的“冷纤维化”以及正常的伤口愈合。该框架阐明了一些无法解释的现象，包括巨噬细胞耗竭的悖论效应，在有限的时间范围内消除炎症导致愈合，以及疤痕成熟需要几个月的时间。我们定义了控制从愈合到纤维化过渡的关键参数，这些参数可以作为治疗性减少纤维化的潜在目标。