Pump it up: bioelectric stimulation controls tissue shape and size

Abstract

Epithelial tissues sheath many organs, separating outside from inside and exquisitely regulating ion and water transport electromechanically to maintain homeostatic balance and tissue hydrostatic pressure. While it is increasingly clear that the ionic microenvironment and external electric stimuli can affect epithelial function and behavior, the coupling between electrical perturbation and tissue form remain unclear. We investigated this by combining electrical stimulation with three-dimensional epithelial tissues with hollow lumens--both kidney cysts and complex intestinal stem cell organoids. Our core finding is that physiological strength electrical stimulation of order 1-3 V/cm (with both direct and alternating currents) can drive powerful and rapid inflation of hollow tissues through a process we call electro-inflation, inducing up to a threefold increase in tissue volume and striking asymmetries in tissue form. Electro-inflation is primarily driven by field-induced ion crowding on the outer surface of the hollow tissue that creates an ion gradient across the epithelial shell, which drives increased ionic flux mediated by ion channels/transporters and subsequent osmotic water flow into the lumen. This influx generates hydrostatic pressure, and inflation results from a competition between this pressure and cell cytoskeletal tension. We validated these interpretations with computational models connecting ion crowding around tissues to tissue mechanics. Electrically stimulated cysts and organoids also exhibited pronounced asymmetry, where the epithelial shell thickened on the cathode-facing side and thinned on the anode-facing side of the tissue. We discovered that this process is the result of 3D electrotaxis-directed migration of cells in an electric field-causing a redistribution of cells around the shell. The ability of electrical cues to dramatically regulate tissue size and shape highlight the key role of the electrical micro-environment and the potential offered by manipulating these signals.