From non-excitable single-cell to multicellular bioelectrical states supported by ion channels and gap junction proteins: Electrical potentials as distributed controllers

Endogenous bioelectric patterns within tissues are an important driver of morphogenesis and a tractable component of a number of disease states. Developing system-level understanding of the dynamics by which non-neural bioelectric circuits regulate complex downstream cascades is a key step towards both, an evolutionary understanding of ion channel genes, and novel strategies in regenerative medicine. An important capability gap is deriving rational modulation strategies targeting individual cells' bioelectric states to achieve global (tissue- or organ-level) outcomes. Here, we develop an ion channel-based model that describes multicellular states on the basis of spatio-temporal patterns of electrical potentials in aggregates of non-excitable cells. The model is of biological interest because modern techniques allow to associate bioelectrical signals with specific ion channel proteins in the cell membrane that are central to embryogenesis, regeneration, and tumorigenesis. As a complementary approach to the usual biochemical description, we have studied four biophysical questions: (i) how can single-cell bioelectrical states be established; (ii) how can a change in the cell potential caused by a transient perturbation of the cell state be maintained after the stimulus is gone (bioelectrical memory); (iii) how can a single-cell contribute to the control of multicellular ensembles based on the spatio-temporal pattern of electrical potentials; and (iv) how can oscillatory patterns arise from the single-cell bioelectrical dynamics. Experimentally, endogenous bioelectric gradients have emerged as instructive agents for morphogenetic processes. In this context, the simulations can guide new procedures that may allow a distributed control of the multicellular ensemble. (C) 2019 Elsevier Ltd. All rights reserved.