Membrane Voltage Changes Control Timing of Stem Cell Differentiation

PLos ONE, November 17

Researchers at Tufts University have discovered that changes in voltage which naturally occur across adult human stem cell membranes act as a powerful control mechanism which determines the timing of stem cell differentiation.

Led by Dr. Michael Levin, the scientists have shed new light on the role that electrophysiology plays in the differentiation and proliferation of stem cells. According to Dr. Levin, "We have found that voltage changes act as a signal to delay or accelerate the decision of a stem cell to drop out of a stem state and differentiate into a specific cell type. This discovery gives scientists in regenerative medicine a new set of control knobs to use in ongoing efforts to shape the behavior of adult stem cells. In addition, by uncovering a new mechanism by which these cells are controlled in the human body, this research suggests potential future diagnostic applications."

Using human mesenchymal stem cells (hMSCs), the researchers examined naturally occurring changes in membrane potential (voltage) in the hMSCs, which were harvested from donor bone marrow. As the hMSCs were differentiating into fat and bone cells, the scientists discovered unique voltage patterns that correspond to each stage of the differentiation process. For example, hyperpolarization, in which the difference between the interior and exterior voltages of a cell increases, was found to be characteristic of cells that had already differentiated, but not of cells that still remained undifferentiated. Additionally, the hMSCs were found to exhibit different membrane potentials depending upon whether they were differentiating into bone or fat cells.

When the researchers depolarized the hMSCs by exposing them to high levels of extracellular ions such as potassium, the artificially induced depolarization was found to disrupt the increase in negative voltage that would otherwise naturally occur during differentiation, which resulted in suppressed differentiation as measured by suppressed fat and bone cell differentiation markers. Converseley, when the researchers treated the hMSCs with hyperpolarizing reagents, the various differentiation markers were found to be upregulated.

All cells throughout the human body are, by their very nature, electrical, and terms which are usually reserved for electronics or electrical engineering, such as "current" and "voltage", are also directly relevant to human physiology. Although biologists do not generally focus much attention on the electrochemistry, nor on the electrophysics, of cellular processes, such electrical phenomena are undeniably at the very essence of organic life. As this study clearly demonstrates, a simple change in voltage across the membrane of a stem cell is all that is required to constitute the "command" that determines whether a stem cell will or will not differentiate.

The Tufts researchers plan to continue further studies to examine in further detail the extent to which hyperpolarization determines the specific types of cells into which a stem cell will differentiate. Ultimately, if scientists could control such electrical processes, cellular differentiation could be used as a therapeutic tool with much greater precision and specificity. Regardless of what, exactly, such future discoveries might reveal, however, the electrodynamics of stem cells is already recognized as playing a vital role in the field of regenerative medicine.

The study was funded in part by the National Science Foundation, the National Institutes of Health, and the U.S. Defense Advanced Research Projects Agency (DARPA). The publication appeared in PLoS ONE, a peer-reviewed, open-access resource of the Public Library of Science.