Direct communication between individual mammalian cells via tunneling nanotube-like structures

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Jin Huh, Sun Chang Kim, Ron Weiss

Intelligent Synthetic Biology Center, South Korea

Cell-to-cell communication has incorporated multicellularity into the existing genetic circuitry, broadening its spectrum of application. It has been successfully applied to both microbial and mammalian systems and achieved complex cellular behaviors such as multicellular computing, synthetic ecosystems, biosensors, and pattern formations. Cell-to-cell communication among engineered cells has so far been based on the quorum sensing inspired system where communication is mediated by signaling molecules secreted by sender cells into the environment and subsequently received by receiver cells. However, the intrinsic properties of this system such as limited types of signaling molecules or confinement of communication in a population level may hinder further utilization for a number of applications. Here we have demonstrated a unique one-to-one communication between individual mammalian cells connected via tunneling nanotubes (TNT)-like structures. A sender cell constructs a membranous tube and connects itself with a receiver cell. Through this conduit, cellular components such as ions, macromolecules, nucleotides, proteins, vesicles, or even organelles, are transported and are capable of acting as signals. As a first step, we have built genetic circuits that modularly control the construction of TNT-like structures and relay signals among cells in vitro. Additionally, carried by Herpes simplex viral capsids, the large genetic circuits themselves are transported from sender cells to receiver cells. This new way of communication will be a critical addition to the existing tool box for creating gene networks that encode artificial developmental programs in mammalian cells and that coordinate the action of cell-level morphogenetic processes in space and time. Moreover, this system can be implemented to develop cancer therapeutic agents with enhanced dissemination rates within the tumor microenvironment.