%0 Journal Article
%T Engineering programmable material-to-cell pathways via synthetic notch receptors to spatially control differentiation in multicellular constructs.
%A Garibyan M
%A Hoffman T
%A Makaske T
%A Do SK
%A Wu Y
%A Williams BA
%A March AR
%A Cho N
%A Pedroncelli N
%A Lima RE
%A Soto J
%A Jackson B
%A Santoso JW
%A Khademhosseini A
%A Thomson M
%A Li S
%A McCain ML
%A Morsut L
%J Nat Commun
%V 15
%N 1
%D 2024 Jul 13
%M 39003263
%F 17.694
%R 10.1038/s41467-024-50126-1
%X 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.