Control of spatio-temporal patterning via cell growth in a multicellular synthetic gene circuit

Marco Santorelli, Pranav S. Bhamidipati, Josquin Courte, Benjamin Swedlund, Naisargee Jain, Kyle Poon, Dominik Schildknecht, Andriu Kavanagh, Victoria A. MacKrell, Trusha Sondkar, Mattias Malaguti, Giorgia Quadrato, Sally Lowell, Matt Thomson () and Leonardo Morsut ()
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Marco Santorelli: University of Southern California
Pranav S. Bhamidipati: Division of Biology and Biological Engineering, California Institute of Technology
Josquin Courte: University of Southern California
Benjamin Swedlund: University of Southern California
Naisargee Jain: University of Southern California
Kyle Poon: University of Southern California
Dominik Schildknecht: Division of Biology and Biological Engineering, California Institute of Technology
Andriu Kavanagh: University of Southern California
Victoria A. MacKrell: University of Southern California
Trusha Sondkar: University of Southern California
Mattias Malaguti: The University of Edinburgh
Giorgia Quadrato: University of Southern California
Sally Lowell: The University of Edinburgh
Matt Thomson: Division of Biology and Biological Engineering, California Institute of Technology
Leonardo Morsut: University of Southern California

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract A major goal in synthetic development is to build gene regulatory circuits that control patterning. In natural development, an interplay between mechanical and chemical communication shapes the dynamics of multicellular gene regulatory circuits. For synthetic circuits, how non-genetic properties of the growth environment impact circuit behavior remains poorly explored. Here, we first describe an occurrence of mechano-chemical coupling in synthetic Notch (synNotch) patterning circuits: high cell density decreases synNotch-gated gene expression in different cellular systems in vitro. We then construct, both in vitro and in silico, a synNotch-based signal propagation circuit whose outcome can be regulated by cell density. Spatial and temporal patterning outcomes of this circuit can be predicted and controlled via modulation of cell proliferation, initial cell density, and/or spatial distribution of cell density. Our work demonstrates that synthetic patterning circuit outcome can be controlled via cellular growth, providing a means for programming multicellular circuit patterning outcomes.

Date: 2024
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DOI: 10.1038/s41467-024-53078-8

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