We generate traveling surface acoustic waves with an interdigital transducer to create droplets on-demand; encapsulate single cells; lyse cells and immediately encapsulate their contents; and pico-inject new materials into existing droplets.
The spatio-temporal patterning of multicellular tissues is driven by the collective dynamics of cell proliferation and active movement. These processes are mediated by the extracellular matrix environment via a combination of biomolecular and physical cues, but how the viscoelastic properties of the matrix regulate collective cell spatial and temporal organization is unknown. Here we show that the passive viscoelastic properties of the matrix that encapsulate a proliferating ball of cells (e.g. a developing organoid) play a critical role in guiding tissue organization in space and time. By varying the viscoelasticity of well-defined model matrices, we show how a spheroidal tissue of breast epithelial cells breaks symmetry and forms finger-like protrusions that invade the matrix. Additionally, matrix viscoelasticity drives epithelial to mesenchymal transition both in vitro and in vivo, and YAP nuclear translocation. A computational model allows us to recapitulate these observations and leads to a phase diagram that demarcates the regions of morphological stability and instability as a function of matrix viscoelasticity, tissue viscosity, cell motility and cell division rate. Experiments that use biomolecular manipulations to independently vary these parameters confirm our predictions. To further test our theory, we also study the self-organization of an in vitro intestinal organoid and show that the morphological changes of this system also fit within our paradigm. Further, we find the collective cell response to matrix viscoelasticity is regulated by the Arp2/3 complex. Altogether, our studies demonstrate the role of stress relaxation mechanisms in determining the dynamics of tissue growth and the symmetry breaking instabilities associated with fingering, a fundamental process in morphogenesis and oncogenesis, and suggest ways of controlling tissue form using the extracellular matrix.
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