BioWorld International Correspondent

LONDON - Human cells use at least two gene products to respond to electric fields created by ion flow, which help to heal wounds, researchers have found. The molecules control a type of cell migration called electrotaxis and activate signaling pathways similar to those identified for chemotaxis.

Min Zhao, professor of biomedical sciences at the School of Medical Sciences and Department of Ophthalmology at the University of Aberdeen in Scotland, told BioWorld International: "These discoveries offer a novel perspective in wound-healing research and management. Endogenous electric fields clearly have a significant role in guiding cell movement in wound healing. This effect is mediated by a couple of key molecules, which have been shown as 'compass molecules' in chemotaxis, the directional cell movement in response to chemical gradients."

Now that the molecules mediating electrotaxis have been identified, he added, it may be possible to develop new approaches to manage wounds clinically. Zhao and his colleagues are collaborating with several clinical teams to develop new treatments.

Zhao said: "At the moment, we are mainly focusing on modulating the endogenous electric fields to find optimal ways of enhancing them, perhaps by developing devices for applying electric fields to wounds. We also want to find out if the drugs we have tried in our lab tests could be used to develop eye drops to help eye wounds or dressings used in the treatment of other wounds."

The work is reported in the July 27, 2006, issue of Nature in a paper titled "Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN." Zhao's collaborators include scientists based in Austria, the U.S. and Japan.

Endogenous electric fields around wounds were first detected more than 150 years ago by the German physiologist Emil Du-Bois Reymond. More recently, studies have shown that disruption of an epithelial layer instantly generates endogenous electric fields, which scientists have proposed are important in wound healing. The electric fields are created by ion pumps, which move ions of positive or negative charge in particular directions.

Zhao and his team set out to investigate how the phenomenon was controlled. Using an in vitro model of a wound in corneal epithelium, without applying an electrical field, they showed that cells moved into the wound in a coordinated manner.

When they applied an electrical field with a polarity opposite to that normally observed in a natural wound, the cells migrated in the opposite direction, and the wound opened up instead of beginning to heal. Increasing the strength of the field (using the normal polarity) increased the speed of cell movement into the wound.

The experiments led Zhao and his collaborators to conclude that electrical signals guide and stimulate the migration of inflammatory cells, fibroblasts and epithelial cells in wound healing.

Their next set of studies showed that electric fields could induce signaling cascades similar to those involved in chemotaxis. Certain signaling molecules became located at the leading edge of migratory cells, when the cells were exposed to an electric field.

A molecule called p110gamma appeared to be important in the process. When Zhao and his colleagues disrupted the copy of the gene encoding p110gamma in the cells, they found that the signaling molecules no longer responded to the electric field in the same way. In particular, when the cells were cultured in assays designed to assess cell migration, the cells no longer migrated in response to an electric field.

Writing in Nature, the team concluded, "These data show that [the protein made by the gene p110gamma] controls electrotaxis and provides the first identification of a gene, p110gamma, that controls electric-field-induced cell migration." Further experiments showed that the product of a gene called phosphatase and tensin homologue (Pten) also is required for electrotaxis-regulated wound healing.

Zhao explained: "We found that the protein encoded by p110gamma, which is called PI3 kinase (gamma) catalytic subunit, when activated, sends a signal down within the cell, which results in actin polymerization. Actin polymerization in turn pushes the cell membrane, enabling the cell to move in that direction."

The second gene, Pten, he said, is a negative regulator of PI3 kinase signaling.

Zhao denies that his Chinese cultural background influenced his professional approach. "I would prefer to say that my pro-collaborative attitude and my enthusiasm for this work brought me again and again face to face with people with doubts and pessimism. Many of these people were very smart, and their criticisms were key propellers to the development of the project," Zhao told BioWorld International.

And does this study tell us anything about how acupuncture might work? Zhao said he thought not. "I think they are only remotely related. But I am going to keep thinking about it until the day we are ready to tackle this with some convincing enough experiments," he said.