Mechanism Identified Behind Impaired Wound Healing in Diabetics

Curated by Claudia Shannon / Research Scientist / ishonest

About 15% of diabetics will have a non-healing wound at some point in their lifetime, and in some cases, these non-healing open ulcers can be so severe that they lead to amputations.

In 2013, a study found – contrary to previous research – that the Foxo1 molecule promotes healing by both protecting cells against oxidative stress and inducing a molecule called TGF-ß1 that is critical for wound healing.

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The Penn team wanted to investigate whether these mechanisms are also implicated in the reduced capacity for wound healing among people with diabetes.

To do this, the researchers first created small wounds on the tongues of mice with diabetes and a control group of non-diabetic mice. The wounds of the diabetic mice – as might be expected – healed more slowly than the control mice.

The team then repeated this experiment in mice bred to lack Foxo1 in a type of cell called keratinocytes, which “fill in” the holes left by injuries. The researchers were surprised to find that the absence of the Foxo1 protein and FOXO1 gene in the keratinocytes appeared to cause the diabetic mice to heal more quickly.

Next, the team experimented with cells in culture. The researchers found that cells grown in a “high-sugar media” were less able to move and proliferate, compared with cells grown in standard solution.

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The same slowed proliferation of cells was observed by the researchers in diabetic mice; because the cells were slow to proliferate, they closed the wound over the keratinocyte filling less quickly than cells in the non-diabetic mice. And, like the diabetic mice, this impaired proliferation was reduced when the researchers silenced Foxo1 in the cells.

FOXO1 fails to stimulate wound-healing molecule in diabetics

Further experiments demonstrated that two signaling molecules regulated by Foxo1, CCL20 and IL-36 are implicated in the reduced cell movement – and by extension, reduced wound healing – found in diabetics.

Although the FOXO1 gene normally stimulates production of the wound-healing molecule TGF-ß1, say the researchers, in the diabetic mice it failed to do so, instead stimulating production of CCL20 and IL-36. These proteins interfere with the migration of keratinocytes, turning FOXO1 from promoting healing to hindering it.

Study leader Dana T. Graves, professor in Penn Dental Medicine’s Department of Periodontics and vice dean for scholarship and research, says:

“In terms of a wound-healing response, it looks like Foxo1 might be one of the central regulators that are affected by the diabetic condition. This may make it a good drug target, which could possibly be administered locally to minimize systemic effects in diabetic wounds.”

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