Marcel Karperien, Martin Peter Neubauer, Paul de Vos, Alexandra M. Smink, Bart J. de Haan, Tom Kamperman, Su Ryon Shin, Herman L. Offerhaus, Wooje Lee, Sieger Henke, Niels G A Willemen, Pieter J. Dijkstra, João F. Crispim, Jeroen Leijten, Man, Biomaterials and Microbes (MBM), Translational Immunology Groningen (TRIGR), TechMed Centre, Developmental BioEngineering, Optical Sciences, and MESA+ Institute
Cell-matrix interactions govern cell behavior and tissue function by facilitating transduction of biomechanical cues. Engineered tissues often incorporate these interactions by employing cell-adhesive materials. However, using constitutively active cell-adhesive materials impedes control over cell fate and elicits inflammatory responses upon implantation. Here, an alternative cell-material interaction strategy that provides mechanotransducive properties via discrete inducible on-cell crosslinking (DOCKING) of materials, including those that are inherently non-cell-adhesive, is introduced. Specifically, tyramine-functionalized materials are tethered to tyrosines that are naturally present in extracellular protein domains via enzyme-mediated oxidative crosslinking. Temporal control over the stiffness of on-cell tethered 3D microniches reveals that DOCKING uniquely enables lineage programming of stem cells by targeting adhesome-related mechanotransduction pathways acting independently of cell volume changes and spreading. In short, DOCKING represents a bioinspired and cytocompatible cell-tethering strategy that offers new routes to study and engineer cell-material interactions, thereby advancing applications ranging from drug delivery, to cell-based therapy, and cultured meat.