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That healing spark

Your biology is electric – literally! Every cell in your body produces tiny electric currents that communicates its health status to other cells, like a little battery [1]. Until recently it was thought that only nerve and muscle cells communicated with electrical signalling. But new research tools, especially voltage-reporting dye, have permitted scientists to observe these electrical impulses in all types of cells. Cell membranes regulate bioelectricity by keeping chemical ions (calcium, sodium and potassium) on different sides, some inside and some outside the cell, to maintain the electric charge. This bioelectricity is essential for co-coordinating and ordering cellular processes, including telling cells how to form organs and body parts as a foetus develops [1].


As our understanding evolves it’s becoming clear that bioelectricity is essential for controlling cell behaviour, including dynamic changes in gene expression, metabolic changes and mechanical cell properties [2]. The implications of bioelectricity for disease are being explored, with exciting developments in understanding cancer growth and metastasis (spread) [1].


Figure: Recent research shows that cells use ion- and redox-based electrochemical signals for communication. It has been shown that such communication enables the organization of growth and developmental processes across multiple length scales [2].


Electric fields are also essential for wound healing, turning on genes and accelerating the production of collagen (scar tissue) and migration and activation myofibroblasts (the source of scar tissue) [3]. Bioelectricity also causes tissue contraction, and coordinates the whole process of wound healing. Immediately after injury there is an increase in current at the edges of the wound which slowly increases. Then, as the wound heals the current decreases until it disappears at the completion of healing [3].


Perhaps that healing spark turns into a wildfire in fibrosis, one that is difficult to extinguish.

It’s known that electrical and internal mechanical forces (from stiff scar tissue pulling against other tissues) act together to stiffen collagen and enable more contractions [2]. Collagen is piezoelectric, so stiff scar tissue converts mechanical stress into electrical signalling [2], meaning that feedback effects probably occur. Perhaps that healing spark turns into a wildfire in fibrosis, one that is difficult to extinguish. This suggests that adding additional electricity such as pulsed electromagnetic fields might be counterproductive in the context of fibrosis.

However, this understanding does point to some interesting therapeutic possibilities. New research suggests that some ion channel blockers that are used to treat heart disease might supress the oscillations of current in cancers, and people taking them are more likely to survive cancer [1]. Similar oscillations of current occur in fibrosis. Calcium influxes are an important aspect of bioelectricity and are known to be have a fundamental role in fibrotic diseases [4]. Calcium influxes are triggered by two key fibrotic growth factors, TGF-β and PDGF4, and TGF-β also upregulates the expression of calcium channels that permit calcium influx. The blockade of one calcium channel, KCa3.1, by a drug called senicapoc (but not dexamethasone) significantly inhibited myofibroblast proliferation, contraction and collagen secretion [4].


Perhaps these medications, or new drugs that alter membrane voltage, will be prescribed to treat fibrosis in the future, but unfortunately, we will have to wait.


References

  1. Adee, S. in New Scientist Vol. 3427 38-41 (2023).

  2. Schofield, Z. et al. Bioelectrical understanding and engineering of cell biology. J R Soc Interface 17, 20200013, doi:10.1098/rsif.2020.0013 (2020).

  3. Yang, J. et al. Bioelectric fields coordinate wound contraction and re-epithelialization process to accelerate wound healing via promoting myofibroblast transformation. Bioelectrochemistry 148, 108247, doi:10.1016/j.bioelechem.2022.108247 (2022).

  4. Roach, K. M. & Bradding, P. Ca(2+) signalling in fibroblasts and the therapeutic potential of K(Ca)3.1 channel blockers in fibrotic diseases. Br J Pharmacol 177, 1003-1024, doi:10.1111/bph.14939 (2020).



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I've just discovered that pregabalin is a calcium channel blocker that regulates calcium influx into cells. This supports the use of pregabalin for treating arthrofibrosis, since it will help regulate the abnormal electrical signals that myofibroblasts give out. It's also used for pain relief, as an anti-convulsant (I've found it very useful for preventing leg cramps) and to assist with sleep.

Kayley

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