Cell circuits of fibroblasts and macrophages depend on organ and disease context

Fibroblasts and macrophages are fundamental components of every organ in the body. They interact to produce either healthy homeostasis or disease states like fibrosis and cancer microenvironments. It is essential to define the principles dictating these outcomes in order to guide the development of treatments. Fibroblast-macrophage interactions can be broadly described as a biological two-cell circuit, defined by their cell numbers, the growth factors they exchange and constraints imposed by their environment. Yet fibroblasts and macrophages evolve to form heterogeneous subpopulations across organs and diseased states, and it is not known whether different organs share similar circuits or whether circuits are tailored for organ-specific tasks. It is also unknown how cancer affects the fibroblast-macrophage circuit. Here we define cell circuits using co-cultures of macrophages and organ-derived fibroblasts from mammary, lung, and fat, and explore the effects of cancer-conditioned medium on the circuits. We develop a mathematical approach to infer circuit parameters from the experimental data, and use this approach to quantitatively compare the various cell circuits. We find that the homeostatic steady-states are strikingly similar between the organs, yet the inferred underlying cell circuits are different. Cancer-conditioned medium profoundly changes the circuit, yielding a state of macrophage self-activation. Transcriptional profiling reveals the molecular underpinnings of these differences, with different families of growth factors composing the interactions in each organ and condition. These findings provide a quantitative approach to define cell interactions in organ-specific scenarios of health and disease.