MECHANOREGULATION OF CELLULAR MEMBRANE VOLTAGE AND BIOELECTRIC GRADIENTS IN EPITHELIAL TISSUES

Abstract

Cancer is a complex, heterogeneous group of diseases that can develop through many routes. It is therefore important to understand how nature coordinates elaborate arrays of regulatory cues into concerted control of growth at the tissue scale. The cellular microenvironment might then be manipulated to drive cells toward a desired outcome at the tissue level. An unexpected parameter, cellular membrane voltage (Vm), which is defined as the electric potential difference between the cytoplasm and external medium, influences a remarkable array of organism-wide patterning events and produces striking outcomes in both tumorigenesis as well as regeneration. These studies suggest that Vm is not only a key intrinsic cellular property, but also an integral part of the microenvironment that acts in both space and time to guide cellular behavior. As a result, there is considerable interest in manipulating Vm to treat disease. However, such manipulations have produced conflicting outcomes experimentally, which poses a substantial barrier to understanding the fundamentals of bioelectrical reprogramming. This is likely due to the multitude of physiological variables that differ between cells and their surroundings. A better understanding of the relation between the cellular microenvironment and Vm is needed.

Here, we investigated the regulation of Vm by mechanical signals. We observed that mechanical stress gradients in mammary epithelial tissues presaged gradients in both proliferation and Vm depolarization, in a manner dependent on Cx43 hemichannels and Yap/Taz nuclear translocation. Additionally, we investigated the relationship between matrix stiffness and Vm by culturing mammary epithelial cells on synthetic substrata, the stiffnesses of which mimicked those of the normal mammary gland and breast tumors. In contrast to previous correlations between increased proliferation and depolarization, we observed that cells are hyperpolarized when cultured on stiff substrata, a microenvironmental condition that enhances proliferation. Together, these results uncover novel roles of mechanical cues in the regulation of bioelectricity and downstream phenotypes.