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

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 Jackson, Jeffrey W. Santoso, Ali Khademhosseini, Matt Thomson, Song Li, Megan L. McCain () and Leonardo Morsut ()
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Mher Garibyan: University of Southern California
Tyler Hoffman: University of California Los Angeles
Thijs Makaske: University of Southern California
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
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
Matt Thomson: California Institute of Technology
Song Li: University of California Los Angeles
Megan L. McCain: University of Southern California
Leonardo Morsut: University of Southern California

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50126-1

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