Figure 2. Emerging toolbox to create regulatory cell-cell interactions.

(A) Schematic illustration of optogenetic chimeric receptors. When cells express these receptors, they respond to light and activate the downstream signaling without a morphogen. Optogenetic chimeric receptors are typically designed as the cytoplasmic regions of morphogen receptors fused with a light-responsible element, such as a light-oxygen-voltage domain. Light triggers hetero- or homodimerization of the receptors, which activates the downstream signaling.

(B) Diagram of synNotch receptor system. synNotch is composed of an extracellular antigen recognition domain, such as scFv, a central regulatory domain in transmembrane domain, and an orthogonal transcription factor (TF). When synNotch detects the antigen on the sender cells (blue), the TF s released by cleavage.

(C) Illustration of synthetic diffusive morphogen system using a synthetic receptor, such as MESA.¹⁹ In this system, synthetic receptor dimerization occurs upon synthetic ligand binding, and such dimerization causes cleavage of the intracellular domain of the receptor, releasing the TF to activate its target gene. In all figures, activated cells are colored in red.

(D) Design of synthetic cell-cell adhesion molecules. Extracellular domains of native adhesion proteins are replaced by specific protein-protein interactions, such as GFP and anti-GFP nanobody.

(E) Multi Fate system is a synthetic circuit that controls multi-fates of mammalian cells for a long term. In MultiFate, TFs (“A” and “B”) homodimerize to self-activate and mutually inhibit one another by heterodimerization.