Principles of Cell Circuits for Tissue Repair and Fibrosis

• Published in: iScience 2020-02, Vol.23 (2), p.100841-100841, Article 100841
• Main Authors: Adler, Miri, Mayo, Avi, Zhou, Xu, Franklin, Ruth A., Meizlish, Matthew L., Medzhitov, Ruslan, Kallenberger, Stefan M., Alon, Uri
• Format: Article
• Language: English
• Subjects: In Silico Biology; Systems Biology; Tissue Engineering
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2020.100841

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. [Display omitted] •A myofibroblast-macrophage circuit for tissue repair shows three physiological states•States correspond to healing, cold fibrosis (lacking macrophages), and hot fibrosis•The circuit explains how a transient/persistent insult leads to healing/fibrosis•The PDGF autocrine loop is a potential target for abrogating fibrosis In Silico Biology; Systems Biology; Tissue Engineering