Circuit design features of a stable two-cell system

Cell communication within tissues is mediated by multiple paracrine signals including growth factors, which control cell survival and proliferation. Cells and the growth factors they produce and receive constitute a circuit, yet the design features of cell circuits involved in tissue homeostasis are unknown. Here we used computational and experimental approaches to characterize the features of cell circuits based on growth factor exchange between macrophages and fibroblasts, two cell types found in most mammalian tissues. We found that the macrophage-fibroblast cell circuit is stable and robust to perturbations. We employed analytical screening of all possible two-cell circuit topologies and defined the circuit features sufficient for stability, including environmental constraint and negative feedback regulation. Moreover, we discovered that cell-cell contact was essential for the stability of the macrophage-fibroblast circuit. These findings highlight general principles of cell circuit design, and provide a new perspective on quantitative understanding of tissue homeostasis. 1 sample of murine embryonic fibroblast and 1 sample murine bone marrow derived macrophages are analyzed for their expression of growth factors and growth factor receptors