Epithelial tissue geometry directs emergence of bioelectric field and pattern of proliferation

Abstract

Patterns of proliferation are templated by both gradients of mechanical stress as well as by gradients in membrane voltage (Vm), which is defined as the electric potential difference between the cytoplasm and external medium. Either gradient could regulate the emergence of the other, or they could arise independently and synergistically affect proliferation within a tissue. Here, we examined the relationship between endogenous patterns of mechanical stress and the generation of bioelectric gradients in mammary epithelial tissues. We observed that the mechanical stress gradients in the tissues presaged gradients in both proliferation and depolarization, consistent with previous reports correlating depolarization with proliferation. Furthermore, disrupting the Vm gradient blocked the emergence of patterned proliferation. We found that the bioelectric gradient formed downstream of mechanical stresses within the tissues and depended on Cx43 hemichannels, which opened preferentially in cells located in regions of high mechanical stress. Activation of Cx43 hemichannels was necessary for nuclear localization of Yap/Taz and induction of proliferation. Together, these results suggest that mechanotransduction triggers the formation of bioelectric gradients across a tissue, which are further translated into transcriptional changes that template patterns of growth.

Calcium, an Emerging Intracellular Messenger for the Hippo Pathway Regulation

“…Inhibition of Ca 2+ influx reduces YAP phosphorylation and increases YAP nuclear localization. In a study of the relationship among patterns of mechanical stress, bioelectric field and proliferation, Silver et al (2020) found that mechanical stress gradients in mammary epithelial tissues of defined geometry lead more YAP/TAZ nuclear localization in cells at the tissue periphery than the center region. This phenomenon was accompanied by an increase of Ca 2+ level in cells at this region.…”

Global feather orientations changed by electric current

“…Biochemical signals may not be sufficient to drive the whole morphogenetic process. Integration with mechanical force and bioelectric signals have been implicated in regulating tissue morphogenesis (McLaughlin and Levin, 2018;Muncie and Weaver, 2018;Silver et al, 2020). To dissect out the morphogenetic control of tissue patterning, we chose a model consisting of a population of mini-organs.…”

Bioengineering in vitro models of embryonic development

“…Review associated with proliferation, apoptosis, or differentiation (Silver et al, 2020). Bioengineering tools can interact with and spatially pattern endogenous electric fields to shepherd collective cell motility in a process known as electrotaxis (Zajdel et al, 2020).…”

“…Besides morphogen signaling, electrical fields created through plasma membrane depolarization can be transmitted between cells via gap junctions or ion channels. Changes in membrane potential can then determine intracellular ion concentrations, affecting signaling networks associated with proliferation, apoptosis, or differentiation ( Silver et al., 2020 ). Bioengineering tools can interact with and spatially pattern endogenous electric fields to shepherd collective cell motility in a process known as electrotaxis ( Zajdel et al., 2020 ).…”