A synthetic multicellular system for programmed pattern formation

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Abstract
Multicellular organisms, and some single-celled organisms, are capable of producing predetermined patterns. Patterning is key to developmental processes, and is also relevant to tissue engineering and biomaterials design. Basu et al. describe a new synthetic multicellular system in which cells are genetically programmed to form patterns on a surface based on cell–cell communication. Genetic circuits were constructed from well defined simple parts in bacteria that integrate transcriptional regulation with cell–cell signalling elements. These circuits transform a lawn of undifferentiated cells into two-dimensional patterns that resemble a bullseye, ellipse, heart and clover. Pattern formation is a hallmark of coordinated cell behaviour in both single and multicellular organisms1,2,3. It typically involves cell–cell communication and intracellular signal processing. Here we show a synthetic multicellular system in which genetically engineered ‘receiver’ cells are programmed to form ring-like patterns of differentiation based on chemical gradients of an acyl-homoserine lactone (AHL) signal that is synthesized by ‘sender’ cells. In receiver cells, ‘band-detect’ gene networks respond to user-defined ranges of AHL concentrations. By fusing different fluorescent proteins as outputs of network variants, an initially undifferentiated ‘lawn’ of receivers is engineered to form a bullseye pattern around a sender colony. Other patterns, such as ellipses and clovers, are achieved by placing senders in different configurations. Experimental and theoretical analyses reveal which kinetic parameters most significantly affect ring development over time. Construction and study of such synthetic multicellular systems can improve our quantitative understanding of naturally occurring developmental processes and may foster applications in tissue engineering, biomaterial fabrication and biosensing.