Design principles of cell circuits with paradoxical components

Abstract

Biological systems display complex networks of interactions both at the level of molecules inside the cell and at the level of interactions between cells. Networks of interacting molecules, such as transcription networks, have been shown to be composed of recurring circuits called network motifs, each with specific dynamical functions. Much less is known about the possibility of such circuit analysis in networks made of communicating cells. Here, we study models of circuits in which a few cell types interact by means of signaling molecules. We consider circuits of cells with architectures that seem to recur in immunology. An intriguing feature of these circuits is their use of signaling molecules with a pleiotropic or paradoxical role, such as cytokines that increase both cell growth and cell death. We find that pleiotropic signaling molecules can provide cell circuits with systems-level functions. These functions include for different circuits maintenance of homeostatic cell concentrations, robust regulation of differentiation processes, and robust pulses of cells or cytokines.G ene regulation networks are composed of a handful of recurring circuit elements, called network motifs (1). Theory and experiments have shown that each network motif can carry out specific dynamical functions in an autonomous way, such as filtering noisy signals, generating output pulses, and speeding responses (1).Here, we ask whether one can apply this approach to the level of circuits made of interacting cells. For this purpose, we consider cells that communicate by means of secreted molecules. These secreted molecules affect cell behaviors such as rate of proliferation and cell death. Previous studies on such cell systems attempted to include many cell types and interactions in a model involving numerous biochemical parameters and variables (2-5). Other works focused on the effects of a single cell type responding, for example, to a ligand that it secretes itself; these works showed the interplay between cell to cell variability and positive feedback, leading to bistability (selection), formation of thresholds for immune response, and memory (6, 7).Here, we study simple models of circuits made of a few communicating cell types. Because many of the interactions in cell circuits are poorly characterized at present, we seek models in which the exact functional form of the interactions does not affect the conclusions; therefore, models have a degree of generality. We also scan all possible topologies with a given set of components to obtain the widest class of circuits that can perform a given function.We consider circuit designs that seem to recur in immunology. An intriguing feature of these systems is the fact that many secreted signaling molecules (cytokines) are pleiotropic: they have multiple effects, sometimes antagonistic or paradoxical, such as increasing both proliferation and death of a certain cell type. We find that pleiotropic signals, in the configurations suggested by immune circuits, can provide circuits with specific d...

Extracellular matrix stiffness causes systematic variations in proliferation and chemosensitivity in myeloid leukemias

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Paradoxical signaling regulates structural plasticity in dendritic spines

“…There are two main sources of robustness in our model, despite the large number of parameters. The first source arises from the paradoxical network structure, which is robust to sloppiness (12,13). The other source of robustness comes from the interplay between the signaling and the cytoskeleton (56).…”

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“…A biexponential function can be used to fit these curves, wherein one exponent corresponds to the timescale of activation and one corresponds to the timescale of inhibition. Hart and coworkers (12,13) identified that network motifs with bifunctional enzymes, which control activation and inhibition, can be thought of as paradoxical, because the same stimulus seems to control the activation and the inhibition in response to the same stimulus. This circuit is a special case of the incoherent feedforward loop (13).…”

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