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Engineering programmable material-to-cell pathways via synthetic notch receptors to spatially control differentiation in multicellular constructs

Author

Listed:
  • Mher Garibyan

    (University of Southern California
    University of Southern California
    University of Southern California)

  • Tyler Hoffman

    (University of California Los Angeles)

  • Thijs Makaske

    (University of Southern California
    University of Southern California
    Utrecht University in the lab of Prof. Dr. Lukas Kapitein)

  • Stephanie K. Do

    (University of Southern California)

  • Yifan Wu

    (University of California Los Angeles)

  • Brian A. Williams

    (California Institute of Technology)

  • Alexander R. March

    (University of Southern California
    University of Southern California)

  • Nathan Cho

    (University of Southern California)

  • Nicolas Pedroncelli

    (University of California Los Angeles)

  • Ricardo Espinosa Lima

    (University of California Los Angeles)

  • Jennifer Soto

    (University of California Los Angeles)

  • Brooke Jackson

    (University of California Los Angeles)

  • Jeffrey W. Santoso

    (University of Southern California)

  • Ali Khademhosseini

    (University of California Los Angeles
    Terasaki Institute for Biomedical Innovation (TIBI))

  • Matt Thomson

    (California Institute of Technology)

  • Song Li

    (University of California Los Angeles
    Los Angeles
    Los Angeles)

  • Megan L. McCain

    (University of Southern California
    University of Southern California)

  • Leonardo Morsut

    (University of Southern California
    University of Southern California
    University of Southern California)

Abstract

Synthetic Notch (synNotch) receptors are genetically encoded, modular synthetic receptors that enable mammalian cells to detect environmental signals and respond by activating user-prescribed transcriptional programs. Although some materials have been modified to present synNotch ligands with coarse spatial control, applications in tissue engineering generally require extracellular matrix (ECM)-derived scaffolds and/or finer spatial positioning of multiple ligands. Thus, we develop here a suite of materials that activate synNotch receptors for generalizable engineering of material-to-cell signaling. We genetically and chemically fuse functional synNotch ligands to ECM proteins and ECM-derived materials. We also generate tissues with microscale precision over four distinct reporter phenotypes by culturing cells with two orthogonal synNotch programs on surfaces microcontact-printed with two synNotch ligands. Finally, we showcase applications in tissue engineering by co-transdifferentiating fibroblasts into skeletal muscle or endothelial cell precursors in user-defined micropatterns. These technologies provide avenues for spatially controlling cellular phenotypes in mammalian tissues.

Suggested Citation

  • Mher Garibyan & Tyler Hoffman & Thijs Makaske & Stephanie K. Do & Yifan Wu & Brian A. Williams & Alexander R. March & Nathan Cho & Nicolas Pedroncelli & Ricardo Espinosa Lima & Jennifer Soto & Brooke , 2024. "Engineering programmable material-to-cell pathways via synthetic notch receptors to spatially control differentiation in multicellular constructs," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50126-1
    DOI: 10.1038/s41467-024-50126-1
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    References listed on IDEAS

    as
    1. Elisa Ruffo & Adam A. Butchy & Yaniv Tivon & Victor So & Michael Kvorjak & Avani Parikh & Eric L. Adams & Natasa Miskov-Zivanov & Olivera J. Finn & Alexander Deiters & Jason Lohmueller, 2023. "Post-translational covalent assembly of CAR and synNotch receptors for programmable antigen targeting," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Fankang Meng & Tom Ellis, 2020. "The second decade of synthetic biology: 2010–2020," Nature Communications, Nature, vol. 11(1), pages 1-4, December.
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