Principles of Cell Circuits for Tissue Repair and Fibrosis
Miri Adler,
Avi Mayo,
Xu Zhou,
Ruth A. Franklin,
Matthew L. Meizlish,
Ruslan Medzhitov,
Stefan M. Kallenberger,
Uri Alon
Affiliations
Miri Adler
Department Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
Avi Mayo
Department Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
Xu Zhou
Howard Hughes Medical Institute Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA
Ruth A. Franklin
Howard Hughes Medical Institute Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA
Matthew L. Meizlish
Howard Hughes Medical Institute Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA
Ruslan Medzhitov
Howard Hughes Medical Institute Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA
Stefan M. Kallenberger
Digital Health Center, Berlin Institute of Health (BIH) and Charité, Berlin 10178, Germany; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
Uri Alon
Department Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel; Corresponding author
Summary: 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. : In Silico Biology; Systems Biology; Tissue Engineering Subject Areas: In Silico Biology, Systems Biology, Tissue Engineering
