Science 361, 156–162 (2018)

In multicellular organisms, signaling networks between cells drive patterns of gene expression that result in morphological changes and organization into complex structures. Using a synthetic Notch (synNotch) receptor system, in which the expression of target genes is driven by ligand–receptor recognition between neighboring cells, Toda et al. engineered cells that self-organize into desired patterns. In their system, different populations of cells express a synNotch ligand or its cognate receptor, with adhesion molecules (cadherins) expressed under control of the synNotch-responsive promoter. When co-cultured, the cells reproducibly self-organize into layered structures, with the arrangement of the various synthetic elements within the cells dictating how many layers are formed. After mechanical disruption, the cells re-assembled into their layered structures, mimicking the ability of tissues to regenerate after injury. Incorporation of a lateral inhibition element enabled bifurcation and self-organization of cells originating from a single genotype, while programming subsets of cells to express different cadherins led to the formation of asymmetric structures. Such engineered self-organizing systems could provide insights into the origins of multicellularity, as well as be used to develop new tissue-like biomaterials.