Engineering de-novo intercellular communication systems in mammalian cells.

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Xavier Duportet, Ron Weiss & Gregory Batt

MIT & INRIA, United States

One of the goals of mammalian synthetic biology is to design new functional organs for therapeutic applications. To survive and function effectively within a multicellular organism, their component cells must act in a coordinated fashion within the organ itself but also interact with the whole organism. It may therefore become critical to engineer short and long range intercellular communication mechanisms for de-novo organogenesis based on genetic reprogramming of cells.
To address this challenge, we developed two different in-vitro synthetic intercellular communication systems in mammalian cells, designed to prevent cross talk with the endogenous cell signaling pathways.
To allow short-range communication, we created a paracrine signaling mechanism by coupling sender cells producing an inert and diffusible plant metabolite via an engineered metabolic pathway; and receiver cells sensitive to the concentration levels of this metabolite. Several promoters/transcription factors were constructed allowing the implementation of various responses.
To allow long-range communication, we hijacked the Rous Sarcoma Virus genome to create virus-like particles, free of viral DNA but specifically carrying an effector protein of interest (recombinase, transcription factor, etc…). We demonstrated the modularity and scalability of this cell-to-cell protein transduction system by integrating multiple signals to perform intercellular logic computation.
We believe these systems will be useful for a very broad range of applications and will fasten the development of therapeutic applications of mammalian synthetic biology.