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, a critical growth factor in wound repair. 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 upstream of TGF-β1 in the signaling 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," Graves 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 specialized microenvironment of a cell in a wound, Graves noted. While FOX01 does indeed promote cell death when it is highly activated, it does the opposite when moderately activated. Which activity it promotes 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.
"If you had a small molecule that increased FOX01 expression, you might be able to upregulate TGF-β1 as well as protect against the oxidative stress associated with wound healing," Graves said.
|Contact: Katherine Unger Baillie|
University of Pennsylvania