A synthetic metabolite-based mammalian inter-cell signaling system.

Functionally well-characterized modular transcription units represent the genetic repertoire for the design of synthetic gene networks operating inside individual mammalian cells. Interconnection of specialized cells to multicellular assemblies that could execute complex computational functions requires synthetic signaling systems, which process and synchronize metabolic information between mammalian cells. In this study we have designed a metabolite-controlled inter-cellular signaling device consisting of a human sender cell line stably engineered for constitutive expression of the human liver-type arginase and a transgenic receiver cell line harboring a synthetic circuit, which produced a human glycoprotein in response to L-arginine levels in the culture medium. Quantitative characterization of the system components enabled precise prediction of l-arginine degradation and product gene expression kinetics and showed that two independent transgenic cell lines could functionally inter-operate to form a metabolite-controlled device which is able to precisely time desired target gene expression. Synthetic gene circuits modulating the transfer of metabolic information from a sender to a receiver cell line may enable the design of synthetic hormone systems supporting communication across multicellular assemblies.