![]() Stable fixed points (black dots) and unstable fixed points (white dots) are shown (the semi-stable cold fibrosis state as split black and white), as is the separatrix (black line) that marks the boundary between the basin of attraction of the healing (gray region) and fibrosis states (the parameter values that are used are listed in Table 1). The Myofibroblast-Macrophage Circuit Shows Multi-stability between a Healing State and Two Fibrosis States (A) Phase portrait of the circuit with reference parameters, in which arrows show the flow rate of change of cell numbers. In Silico Biology Systems Biology Tissue Engineering.Ĭopyright © 2020 The Author(s). We define key parameters that control the transition from healing to fibrosis, which may serve as potential targets for therapeutic reduction of fibrosis. 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 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. 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. ![]() To pinpoint the dynamic mechanisms underlying fibrosis, it is important to understand the principles of the cell circuits that carry out tissue repair. Tissue repair is a protective response after injury, but repetitive or prolonged injury can lead to fibrosis, a pathological state of excessive scarring.
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