Skin provides a first line of defense against viruses, bacteria and parasites that might otherwise make people ill. When an injury breaks that barrier, a systematic chain of molecular signalling launches to close the wound and re-establish the skin’s layer of protection.
A study led by researchers from the University of Pennsylvania’s School of Dental Medicine and published in the Journal of Cell Biology now offers a clearer explanation of the role of one of the players in the wound-healing process, a molecule called FOX01. Contrary to what had been expected, FOX01 is critical to wound healing, providing researchers with a possible new target for drugs that could help speed that process for people with impaired wound healing.
A critical element of wound healing involves the movement of keratinocytes. Previous research had found that FOX01 was expressed at higher levels in wounds, but scientists did not understand what role the molecule was playing. In other scenarios, FOX01 promotes cell death and interferes with the cell reproduction — two actions that would seem to be detrimental to healing.
To investigate the role of FOX01 in wound healing, Dana Graves and colleagues bred mice that lacked the protein in their keratinocytes and then observed the wound healing process in these mice compared to mice with normal FOX01. The mice that lacked FOX01 showed significant delays in healing. While all wounds on control mice were healed after 1 week, all of the experimental mice still had open wounds.
Digging deeper into this counterintuitive finding, the researchers examined the effect of reducing FOX01 levels on other genes known to play a role in cell migration. They found that many of these genes were significantly reduced, notably TGF-β1. When the team added TGF-β1 to cells lacking FOX01, the cells behaved normally and produced the proper suite of molecules needed for healing, indicating that FOX01 acts up-stream of TGF-β1 in the signalling pathway triggered during the healing process.
Further experimenting revealed that mice lacking FOX01 had evidence of increased oxidative stress, which is detrimental to wound healing.
‘The wound healing environment is a stressful environment for the cell,’ said senior author Dana Graves, professor in Penn Dental Medicine’s Department of Periodontics and Vice Dean for scholarship and research said. ‘It appears that upregulation of FOX01 helps protect the cell against oxidative stress.’
The fact that FOX01 behaves in this unexpected way could have to do with the specialised microenvironment of a cell in a wound. While FOX01 does indeed promote cell death when it is highly activated, it does the opposite when moderately activated. The activity promoted depends on the environment in which it is acting.
Taken together, the study’s findings demonstrate that FOX01 plays an integral role in two key processes in wound healing: activation of TGF-β1 and protecting the cell against oxidative damage. Its involvement in these aspects of healing make it a potential target for pharmaceuticals that could help speed healing.