Abstract
Simple SummaryElectric potential patterns across tissues are instructive for development, regeneration, and tumorigenesis because they can influence transcription, migration, and differentiation through biochemical and biomechanical downstream processes. Determining the origins of the spatial domains of distinct potential, which in turn decide anatomical features such as limbs, eyes, brain, and heart, is critical to a mature understanding of how bioelectric signaling drives morphogenesis. We studied theoretically how connexin proteins with different voltage-gated gap junction conductances can maintain multicellular regions at distinct membrane potentials. We analyzed a minimal model that incorporates effective conductances ultimately related to specific ion channel and junction proteins that are amenable to external regulation. We also consider a bioelectrical relationship between the connexin composition of the intercellular gap junction and different stages of cancer.Electric potential distributions can act as instructive pre-patterns for development, regeneration, and tumorigenesis in cell systems. The biophysical states influence transcription, proliferation, cell shape, migration, and differentiation through biochemical and biomechanical downstream transduction processes. A major knowledge gap is the origin of spatial patterns in vivo, and their relationship to the ion channels and the electrical synapses known as gap junctions. Understanding this is critical for basic evolutionary developmental biology as well as for regenerative medicine. We computationally show that cells may express connexin proteins with different voltage-gated gap junction conductances as a way to maintain multicellular regions at distinct membrane potentials. We show that increasing the multicellular connectivity via enhanced junction function does not always contribute to the bioelectrical normalization of abnormally depolarized multicellular patches. From a purely electrical junction view, this result suggests that the reduction rather than the increase of specific connexin levels can also be a suitable bioelectrical approach in some cases and time stages. We offer a minimum model that incorporates effective conductances ultimately related to specific ion channel and junction proteins that are amenable to external regulation. We suggest that the bioelectrical patterns and their encoded instructive information can be externally modulated by acting on the mean fields of cell systems, a complementary approach to that of acting on the molecular characteristics of individual cells. We believe that despite the limitations of a biophysically focused model, our approach can offer useful qualitative insights into the collective dynamics of cell system bioelectricity.
Highlights
Patterns in biology result from the interplay between biochemical [1] and biomechanical [2] signals that establish spatio-temporal correlations in multicellular aggregates.In addition, a complementary distributed control based on the cell membrane bioelectricity is emerging [3,4,5,6,7]
The connexin proteins forming the gap junction channels allow the latter communication by the exchange of biochemical and electrical signals between adjacent cells [5,7,9,10,11,12,13,14]
We describe the bioelectrical patterns that result from different decreases of the junction conductance (Figure 3, top)
Summary
Patterns in biology result from the interplay between biochemical [1] and biomechanical [2] signals that establish spatio-temporal correlations in multicellular aggregates. In the case of bioelectrical coupling, it has been shown that multicellular mean fields can collectively influence downstream transcriptional processes via the spatio-temporal maps of biochemical messengers which are dictated by the local electric potentials [3,4,5,7,15]. Our bioelectrical approach can be applied to interconnected smooth muscle cells that propagate signals over relatively long distances [26] It permits both stationary and oscillating patterns [5,27], providing useful insights into a variety of multicellular systems including syncytia of astrocytes [4,28]. We consider only the junctional role of connexin proteins as transducers of electrical signals, disregarding additional biochemical and biomechanical effects that can be relevant in other contexts
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