The big five in fibrosis: Macrophages, myofibroblasts, matrix, mechanics, and miscommunication.

Scarring is part of the normal healing response to tissue injury in all organs and required to rapidly repair acute damages, mostly with extracellular matrix. A variety of different cells are activated into myofibroblasts to produce and remodel the scar matrix. Temporal and spatial coordination of myofibroblast activities with inflammatory macrophages is crucial for the controlled healing process. Miscommunication can result in either insufficient (chronic) or exacerbated (fibrotic) repair. In addition to soluble biochemical signals and intercellular contacts, cell-to-cell communication is mediated by biophysical and chemical signals transmitted through the extracellular matrix. Over the course of healing, the matrix takes over the role of a master coordinator; failure to do so produces poor healing outcomes that reduce organ function. Understanding the mechanical and chemical state of the matrix and its effects on cellular processes will be essential to address diseases that are characterized by dysfunctional matrix, such as fibrosis.