{Reference Type}: Journal Article
{Title}: Engineering programmable material-to-cell pathways via synthetic notch receptors to spatially control differentiation in multicellular constructs.
{Author}: Garibyan M;Hoffman T;Makaske T;Do SK;Wu Y;Williams BA;March AR;Cho N;Pedroncelli N;Lima RE;Soto J;Jackson B;Santoso JW;Khademhosseini A;Thomson M;Li S;McCain ML;Morsut L;
{Journal}: Nat Commun
{Volume}: 15
{Issue}: 1
{Year}: 2024 Jul 13
{Factor}: 17.694
{DOI}: 10.1038/s41467-024-50126-1
{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.