Programming Multicellular Assembly with Synthetic Cell Adhesion Molecules - Nature.com

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Abstract

Cell adhesion molecules are ubiquitous in multicellular organisms, specifying precise cell-cell interactions in processes as diverse as tissue development, immune cell trafficking, and wiring of the nervous system.^1–4 Here, we show that a wide array of synthetic cell adhesion molecules (synCAMs) can be generated by combining orthogonal extracellular interactions with intracellular domains from native adhesion molecules, such as cadherins and integrins. The resulting molecules yield customized cell-cell interactions with adhesion properties similar to native interactions. The synCAM intracellular domain identity dominates in specifying interface morphology and mechanics, while diverse homotypic or heterotypic extracellular interaction domains independently specify the connectivity between cells. This toolkit of orthogonal adhesion molecules enables rationally programmed assembly of novel multicellular architectures, as well as systematic remodeling of native tissues. The modularity of synCAMs provides fundamental insights into how distinct classes of cell-cell interfaces may have evolved. Overall, these tools offer powerful new capabilities for cell and tissue engineering and for systematically studying multicellular organization.

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Author information

Author notes

1. Wesley L. McKeithan

   Present address: Maze Therapeutics, South San Francisco, CA, USA

2. Andrew R. Harris

   Present address: Department of Mechanical and Aerospace Engineering, Carleton University, Ottawa, ON, Canada

Authors and Affiliations

1. UCSF Cell Design Institute, University of California, San Francisco, CA, USA

   Adam J. Stevens, Josiah Gerdts, Ki H. Kim, Wesley L. McKeithan & Wendell A. Lim

2. Dept. of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA

   Adam J. Stevens, Josiah Gerdts, Ki H. Kim, Jonathan T. Ramirez, Wesley L. McKeithan, Faranak Fattahi & Wendell A. Lim

3. Center for Cellular Construction, University of California, San Francisco, CA, USA

   Adam J. Stevens, Andrew R. Harris, Josiah Gerdts, Ki H. Kim, Wesley L. McKeithan, Daniel A. Fletcher & Wendell A. Lim

4. Dept. of Neurology, Weill Institute for Neuroscience, University of California, San Francisco, CA, USA

   Josiah Gerdts

5. Dept. of Bioengineering, University of California, Berkeley, CA, USA

   Andrew R. Harris & Daniel A. Fletcher

6. Dept. of Mechanical and Aerospace Engineering, Carleton University, Ottawa, ON, Canada

   Andrew R. Harris

7. Chan Zuckerberg Biohub, San Francisco, CA, USA

   Daniel A. Fletcher

8. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA

   Jonathan T. Ramirez & Faranak Fattahi

9. Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, CA, USA

   Coralie Trentesaux & Ophir D. Klein

10. Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Ophir D. Klein

Authors

1. Adam J. Stevens
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2. Andrew R. Harris
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3. Josiah Gerdts
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4. Ki H. Kim
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5. Coralie Trentesaux
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6. Jonathan T. Ramirez
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7. Wesley L. McKeithan
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8. Faranak Fattahi
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9. Ophir D. Klein
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10. Daniel A. Fletcher
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11. Wendell A. Lim
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Corresponding author

Correspondence to Wendell A. Lim.

Supplementary information

Reporting Summary

Supplementary Table 1

SynCAM cell-cell-interfaces. Contact angle and GFP enrichment measurements are provided. Error = 95% CI.

Supplementary Table 2

Sequences of protein constructs used in this study. The epitope tag is highlighted in red, the ECD binding region in blue, and TM and ICD in bold.

Supplementary Table 3

SLiM domains from CAM ICDs used in synCAMs. SLiMs were identified from ELM database and literature sources.

Supplementary Video 1

Self-assembly of cells with orthogonal synCAM pairs. Alternative ECD with ICAM-1 ICD are shown (linked to main Fig. 4a).

Supplementary Video 2

Three-cell synCAM interaction network. Three-cell synCAM interaction networks drive cell assembly (linked to main Fig. 4b).

Supplementary Video 3

SynCAM intercalation into native assemblies. Anti-PCAD synCAM (ICAM-1 ICD) drives cell intercalation into PCAD cluster (linked to main Fig. 4e).

Supplementary Video 4

Remodeling Tissue Organization. SynCAMs can drive coupling and complex remodeling of epithelial and spheroid tissues (linked to main Fig. 5b).

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Stevens, A.J., Harris, A.R., Gerdts, J. et al. Programming Multicellular Assembly with Synthetic Cell Adhesion Molecules. Nature (2022). https://ift.tt/JtlTVfb

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• Received: 27 January 2022

• Accepted: 02 December 2022

• Published: 12 December 2022

• DOI: https://ift.tt/JtlTVfb

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