Engineering a Scalable and Orthogonal Platform for Synthetic Communication in Mammalian Cells

Anna-Maria Makri Pistikou; Glenn A.O.  Cremers; B.L. Nathalia; Tom Meuleman; Bas Bögels; B.V. Eijkens; A. de Dreu; Maarten Bezembinder; Oscar M.J.A. Stassen; Carlijn V.C. Bouten; Maarten Merkx; Roman Jerala; Tom F.A. de Greef

doi:10.1038/s41467-023-42810-5

Engineering a Scalable and Orthogonal Platform for Synthetic Communication in Mammalian Cells

Anna-Maria Makri Pistikou, Glenn A.O. Cremers, B.L. Nathalia, Tom Meuleman, Bas Bögels, B.V. Eijkens, A. de Dreu, Maarten Bezembinder, Oscar M.J.A. Stassen, Carlijn V.C. Bouten, Maarten Merkx, Roman Jerala, Tom F.A. de Greef (Corresponding author)

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

The rational design and implementation of synthetic mammalian communication systems can unravel fundamental design principles of cell communication circuits and offer a framework for engineering of designer cell consortia with potential applications in cell therapeutics. Here, we develop the foundations of an orthogonal, and scalable mammalian synthetic communication platform that exploits the programmability of synthetic receptors and selective affinity and tunability of diffusing coiled-coil peptides. Leveraging the ability of coiled-coils to exclusively bind to a cognate receptor, we demonstrate orthogonal receptor activation and Boolean logic operations at the receptor level. We show intercellular communication based on synthetic receptors and secreted multidomain coiled-coils and demonstrate a three-cell population system that can perform AND gate logic. Finally, we show CC-GEMS receptor-dependent therapeutic protein expression. Our work provides a modular and scalable framework for the engineering of complex cell consortia, with the potential to expand the aptitude of cell therapeutics and diagnostics.

Original language	English
Article number	7001
Number of pages	16
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-42810-5
Publication status	Published - Dec 2023

Funding

The authors thank R. Driessen for useful discussions regarding stable transfections, Jesse Lentjes for her help with protein expression, and Indra Van Zundert for her help with confocal microscopy experiments. The authors would like to thank Leo Scheller and Martin Fussenenger for providing the original GEMS and reporter plasmids and the TU-Eindhoven iGEM 2022 team for providing us with the PLS13-IL-10 plasmid. This work was supported by the European Research Council (ERC project no. 101000199 AMIGA, awarded to T.F.A.d.G.) grant, the European Research Council (ERC project no. 899259 MaCChines, awarded to R.J.) grant, and by grants from the Slovenian Research and Innovation Agency (P4-0176, J7-4493, J1-2481, awarded to R.J.).

Funders	Funder number
H2020 European Research Council	899259, 101000199

Keywords

Animals
Receptors, Artificial
Protein Engineering
Peptides/chemistry
Cell Communication
Synthetic Biology
Mammals

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10.1038/s41467-023-42810-5

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Makri Pistikou, A.-M., Cremers, G. A. O., Nathalia, B. L., Meuleman, T., Bögels, B., Eijkens, B. V., de Dreu, A., Bezembinder, M., Stassen, O. M. J. A., Bouten, C. V. C., Merkx, M., Jerala, R., & de Greef, T. F. A. (2023). Engineering a Scalable and Orthogonal Platform for Synthetic Communication in Mammalian Cells. Nature Communications, 14(1), Article 7001. https://doi.org/10.1038/s41467-023-42810-5

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Engineering a Scalable and Orthogonal Platform for Synthetic Communication in Mammalian Cells

Abstract

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Keywords

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Mammalian synthetic biology

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Engineering a Scalable and Orthogonal Platform for Synthetic Communication in Mammalian Cells

Abstract

Funding

Keywords

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Fingerprint

Research areas

Mammalian synthetic biology

Cite this