Tissue processes involve communication between several cell types by means of diverse secreted factors and cell contact signals. This communication allows tissues to maintain homeostasis of cell-type ratios and to respond properly to perturbations such as injury and inflammation. In my talk, I will discuss principles of cell circuits in homeostasis and away from homeostasis as in tissue repair.

Tissue repair is normally a protective response after injury. However, repetitive injury can lead the repair response to produce fibrosis, a pathological state of excessive scarring that affects millions of patients. It is unclear how the repair response can generate drastically different outcomes – proper healing or fibrosis. To understand the transition from protective tissue repair to pathological fibrosis, we examine the communication circuit between the two cell types that play major roles in the repair response: myofibroblasts and inflammatory macrophages. These cell types interact through production of growth factors and other signals to modulate each other’s growth and activity. Understanding the principles of such cell circuits is important in order to pinpoint the dynamic mechanisms underlying tissue repair and fibrosis. We study mathematically the myofibroblast-macrophage circuit and the accumulation of scar-forming extracellular matrix produced and degraded by the cells, in response to injury. We find that fibrosis due to repeated injury results from a bistability between two steady-state outcomes, fibrosis and healing. This cell-circuit framework clarifies several unexplained phenomena including the limited time window in which removing inflammation leads to healing and the paradoxical effect of macrophage depletion in fibrotic settings. Finally, we define the key parameters that control the transition to irreversible fibrosis, in order to identify potential targets for therapeutic reduction or reversal of fibrosis.