The nervous system is often considered the body’s wiring, sending electrical signals to communicate needs and hazards between different parts of the body. However, researchers at the University of Massachusetts at Amherst have now also measured bioelectronic signals propagating from cultured epithelial cells, as they respond to a critical injury.
“Cells are pretty amazing in terms of how they are making collective decisions, because it seems like there is no centre, like a brain,” says researcher Sunmin Yu, who likens epithelial cells to ants in the way that they gather information and solve problems. Alongside lab leader Steve Granick, Yu reports this latest finding in Proceedings of the National Academy of Sciences, suggesting a means for the communication between cells that enables them to coordinate with each other.
While neurons function by bioelectric signals, and punctuated rhythmic bioelectrical signals allow heart muscle cells to keep the heart pumping blood throughout our body, when it comes to intercell signals for any other type of cell, the most common hypothesis is the exchange of chemical cues. Yu, however, had noted from previous work by other groups that the process of “extruding” wounded epithelial cells to get rid of them involved increased expression of the relevant proteins at some distance from the wound itself.
“Our thought process was to inquire about the mechanism by which information could be transmitted over the necessary long distance,” says Yu. She realised that common molecular signalling mechanisms, such as extracellular signal-regulated kinase 1/2 (ERK), which has a speed of around 1 mm/s, would be rather slow as a potential conduit.
Epithelial signals measure up
Yu and Granick grew a layer of epithelial cells on a microelectrode array (MEA). While other approaches to measuring electrical activity in cultured cells exist, an MEA has the advantage of combining electrical sensitivity with a long range, enabling the researchers to collect both temporal and spatial information on electrical activity. They then “wounded” the cells by exposing them to an intense focused laser beam.
Following the wound, the researchers observed electrical potential changes with comparable amplitudes and similar shapes to those observed in neurons, but over much longer periods of time. “The signal propagation speed we measured is about 1000 times slower than neurons and 10 times faster than ERK,” says Yu, expressing great interest in whether the “high-pitch speaking” neurons and heart tissue cells communicate with these “low-pitch speaking” epithelial cells, and if so, how.
The researchers noted an apparent threshold in the amplitude of the generated signal required for it to propagate. But for those that met this threshold, propagation of the electric signals spanned regions up to 600 µm for as long as measurements could be recorded, which was 5 h. Given the mechanical forces generated during “cell extrusion”, the researchers hypothesized the likely role of mechanosensitive proteins in generating the signals. Sure enough, inhibiting the mechanosensitive ion channels shut down the generation of electrical signals.
Yu and Granick highlight previous suggestions that electrical potentials in epithelial cells may be important for regulating the coordinated changes that take place during embryogenesis and regeneration, as well as being implicated in cancer. However, this is the first observation of such electrical potentials being generated and propagating across epithelial tissue.
“Yu and Granick have discovered a remarkable new form of electrical signalling emitted by wounded epithelial cells – cells traditionally viewed as electrically passive,” says Seth Fraden, whose lab at Brandeis University in Massachusetts in the US investigates a range of soft matter topics but was not involved in this research.
Fraden adds that it raises an “intriguing” question: “What is the signal’s target? In light of recent findings by Nathan Belliveau and colleagues, identifying the protein Galvanin as a specific electric-field sensor in immune cells, a compelling hypothesis emerges: epithelial cells send these electric signals as distress calls and immune cells – nature’s healers – receive them to rapidly locate and respond to tissue injuries. Such insights may have profound implications for developing novel regenerative therapies and bioelectric devices aimed at accelerating wound healing.”
Adam Ezra Cohen, whose team at Harvard University in the US focuses on innovative technology for probing molecules and cells, and who was not directly involved in this research, also finds the research “intriguing” but raises numerous questions: “What are the underlying membrane voltage dynamics? What are the molecular mechanisms that drive these spikes? Do similar things happen in intact tissues or live animals?” he asks, adding that techniques such as patch clamp electrophysiology and voltage imaging could address these questions.
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