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  • br Conflict of interest br

    2022-01-15


    Conflict of interest
    Transparency document
    Acknowledgements We acknowledge our funding sources from the American Heart Association (13EIA4480016) and the National Institute of Health/National Heart, Lung, and Blood Institute (RO1 HL094414). We are very grateful to Dr. Shaohua Xiao and Dr. Shan-Shan Zhang for their significant contributions to figure's preparation.
    Introduction Multicellular processes occurring at different spatio-temporal scales underlay formation of the complex patterns characteristic of embryogenesis, regeneration, and tumorigenesis. While single-cell genetics are central to these processes, intercellular interactions must also be incorporated in the conceptual framework as regulative development and regeneration both work toward the construction and repair of complex anatomical target states [[1], [2], [3]]. Recent work suggests that these interactions are mediated not only by biochemical signals but also by bioelectrical ones [[4], [5], [6]]. For instance, the activity of native ion channel and pump proteins give rise to dynamic spatio-temporal differences in these signals (bioelectric pre-patterns), which can contribute to the modulation of gene expression and cellular activity during morphogenesis. Several laboratories have characterized the roles of endogenous bioelectric patterns as instructive cues for eye induction, neural tissue patterning and BGB324 size control, axial polarity, appendage regeneration, and carcinogenesis in model animal species as well as in human channelopathies [[7], [8], [9], [10], [11]]. Bioelectric signaling is being revealed as a powerful mechanism by which organisms may coordinate patterning across distances and harness individual behaviors of stem and somatic cells toward large-scale patterning outcomes [12]. In general, there exists an electrical potential difference between the cell cytoplasm and the extracellular environment -the membrane potential Vmem [13]. Dynamic (time-dependent) and resting (steady-state) values of Vmem constitute an important readout of cell state. For instance, the ion channels that regulate Vmem are also involved in tumor initiation and metastasis [5,11,[14], [15], [16]] and cancerous cells tend to show abnormal potentials. External actions aimed at restoring the normal potentials could play a role in tumor normalization [11,14,15], as they do in stem cell differentiation [17,18]. Note also that Vmem can influence the spatio-temporal concentrations of many charged signaling molecules and ions, e.g., by cytosolic calcium regulation through voltage-gated calcium channels or by altering neurotransmitter transport rates that are crucial to downstream genetic processes [1,4,[6], [7], [8], [9], [10], [11]]. Therefore, the electric potential regulation of the local concentrations and activities of these signaling molecules and ions over the multicellular domain can influence the transcription and post-translational processes. Could the combined dynamics of molecular biology and bioelectricity suggest new approaches to the rational control of growth and form? Bioelectric control of morphogenesis would complement the current focus on biochemical concepts and genetic networks, with significant implications for regenerative medicine of birth defects, traumatic injury, and cancer. For instance, robust developmental self-assembly and organ regeneration require exquisite dynamical control of complex anatomical structures [19]. How is this achieved? While positional information concepts and reaction-diffusion models are central to biological patterns [[20], [21], [22]], diffusion gradients alone can face limitations [[23], [24], [25]]; evolution has exploited the assistance of biomechanical and bioelectrical fields in order to establish and maintain the spatio-temporal order characteristic of biological organization [25,26]. In particular, the concerted action of biochemical and bioelectrical signals can be robust enough to contribute efficient functions over multiple spatio-temporal scales [7,[27], [28], [29], [30], [31], [32]]. One of the key areas for advances in the exciting field of developmental bioelectricity is the study of quantitative physical models that facilitate spatio-temporal control and guide self-assembly of the endogenous patterns of cell electric potentials [4,[32], [33], [34], [35], [36]].