Understanding and Controlling Collective Cell Behavior: A Study of Supracellular Dynamics in Epithelial Tissues

Abstract

The ability to program collective cell migration empowers us to control critical multicellular processes in development, regenerative medicine, and disease. In these complex processes, coordination is needed across multiple time and length scales, from the cellular level through tissue-tissue assembly in an organism. In wound healing particularly, two previously homeostatic tissues must (1) sense a signal to migrate into the wound, (2) polarize and collectively migrate, and (3) converge to a new equilibrium. In the quest to expedite this, or control other migratory processes, this dissertation explores systemic impacts of controlling a single epithelial tissue's 10,000+ collectively-interacting cells via one global transient bioelectric 'command', and then explores multi-tissue convergence dynamics via the interaction and relaxation of colliding tissues. In our investigation of a single collective, we globally directed motion via electrotaxis and showed tissues develop distinct rear, middle, side, and front responses, expressing supracellularity. Furthermore, in post-stimulation relaxation, tissues equilibrated to a new migratory state, with altered neighbor-neighbor interactions and group velocity patterning. In fact, programmed migration reset the tissue's mechanical state, which we confirmed with transient chemical disruption of cell-cell junctions, analysis of strain wave propagation, and quantification of cellular crowd dynamics. Next, we determined rules to predict shape and boundary changes during tissue-tissue collisions. We demonstrated with a physical model that genetically-identical tissues displace each other based on pressure gradients, which are directly linked to cell density gradients. This framework allowed us to estimate the tissue's bulk modulus and design self-assembling complex tessellations from tissue arrays. Finally, we examined heterotypic collisions with model cancer cells, where tissue-tissue interactions are less predictable, and evaluated its implications and potential to improve our biophysical model. This dissertation demonstrates how externally driving collective migration can reprogram baseline cell-cell interactions and collective dynamics, even well beyond the end of global migratory cues. Our conclusions emphasize the importance of a time-dependent supracellular framework to connect the individual cellular interactions to the entire tissue-scale dynamics. By combining this supracellular framework with the biomechanics that underlie tissue-tissue dynamics, we can harness self-assembly techniques and migratory command-response behavior to improve regenerative medicine and engineer living materials.