Collective Behaviors in Exogenously Controlled Epithelia

Mammalian cells leverage collective behaviors to coordinate movement, force production, and fluid pumping during a range of crucial biological processes. These collective behaviors are essential for establishing and maintaining homeostasis and require constitutive cells to accurately sense and respond to their environment. Whereas these collective behaviors are relatively well-studied in the context of confined and freely migrating mature epithelia, it remains poorly understood how they are modulated by exogenous cues. The work presented addresses this gap in knowledge by directly measuring collective behaviors in exogenously controlled epithelial tissues. First, we present data showing that short-term bioelectric stimulation of an epithelium has long-lasting effects on collective migration in the system. We explore the spatiotemporal dynamics of migrational speed, alignment, and correlation in distinct regions of the tissue before, during, and after bioelectric stimulation. These data show that epithelia exhibit an inhomogeneous response to a homogeneous cue. We then show that bioelectric stimulation can be used in a 3D context to control fluid pumping and migration in a lab-grown kidney model via a process we call ‘electro-inflation’. We performed inhibition assays and developed a continuum model to show that electro-inflation is driven by ion crowding and mediated by a balance between ion channel activity and cytoskeletal mechanics. We then generalize our study of collective behavior to exogenous cues outside of bioelectricity by presenting a bioengineered system wherein cells are forced to adhere to their substrate via cadherins – a family of proteins used exclusively in cell-cell junctions. We show that this bio-inspired functionalized system directly modulates force propagation, migrational state, and cell-cycling in the epithelium. Finally, we present ongoing work on mapping the spatiotemporal expenditure of mechanical energy in epithelia using a combination of traction force microscopy and modeling. We show that energy expenditure in epithelia is spatiotemporally patterned, scales with tissue size, and actively regulates migration.