Researchers map epigenetic cause of slowed diabetic wound healing.


A protein that normally fosters tissue repair instead acts to inhibit healing when sugar levels are high, according to a study in The Journal of Cell Biology. The data findings show that the role reversal helps explain why wounds heal slowly in people with diabetes.

The team, from the University of Pennsylvania, state that for diabetes patients, even a cut or scrape can result in severe complications. Because the skin doesn’t close promptly, bacteria can get a foothold in the injured tissue, leading to chronic ulcers that in some cases require amputations. In a previous study the lab found that the protein FOXO1 orchestrates an important early step in healing by promoting the skin cells known as keratinocytes to migrate into the injury, thus building an epithelial layer to cover the wound.

The results showed that FOXO1 spurs their movement by binding to the promoter of TGFB1, a gene that encodes transforming growth factor beta 1 (TGF-β1), a protein that triggers pro-healing responses. FOXO1 levels rise in wounds of diabetic mice, however, to date previous studies have not determined whether the high sugar levels in these animals alter the protein’s function during healing.

To answer this question, the current study compared the healing capabilities of control mice and mice that lack FOXO1 in their keratinocytes. In animals with normal blood sugar, small skin wounds mended more slowly in the absence of FOXO1. But in mice that had diabetes, wounds healed faster if FOXO1 was missing. Seven days after diabetic animals were injured, the wounds were mostly closed in the animals lacking FOXO1 but remained mostly open in the group that still produced FOXO1.

The data findings showed that in the presence of high glucose levels, FOXO1 slows keratinocyte migration. They determined that sugar changes FOXO1’s relationship with TGF-β. At normal sugar levels, cultured keratinocytes produced 45% less TGF-β if they were missing FOXO1. But at high sugar concentrations, cells’ FOXO1 status had no impact on their TGF-β production, suggesting that FOXO1 no longer regulates TGF-β under these conditions. High sugar levels prevented FOXO1 from binding to the TGFB1 promoter, the researchers found. Instead, FOXO1 turns on two genes that curb keratinocyte migration and block wound healing when expressed at high levels.

People with diabetes often produce too little insulin, and the researchers showed that the hormone counteracts FOXO1. For example, high glucose levels boost production of FOXO1, but the researchers found that insulin reversed this effect. The hormone also sped up migration of keratinocytes cultured in high-sugar conditions in the current study.

Two other metabolic malfunctions common in diabetes patients also impede wound healing through FOXO1, the researchers discovered. As blood sugar levels rise, glucose can glom onto proteins and alter their functions. The team found that one glucose-modified protein prevented FOXO1 from attaching to TGFB1‘s promoter, thereby slowing keratinocyte movement. Moreover, levels of the inflammation-promoting molecule TNFα are often high in diabetics. The researchers determined that TNFα similarly blocked FOXO1’s interaction with the TGFB1 promoter and inhibited keratinocyte migration.

The team state that whether FOXO1 is beneficial or harmful, whether it promotes healing or inhibits healing, depends on the environment of the cell.  The team surmise that previous studies showed that insulin stimulates wound healing in diabetics and these data findings support further tests of this potential treatment and suggest that inhibiting FOXO1 could speed healing in patients with diabetes.

Source:  University of Pennsylvania 

In skin from mice with normal glucose levels (top row), more skin cells (red) migrate into damaged tissue in control mice (left) than in mice lacking FOXO1 (right). But in diabetic mice (bottom row), more skin cells migrate into the wound in animals lacking FOXO1 (right) than in controls (left). Blue marks cell nuclei, and the dotted line delineates the boundary between the epidermis and the dermis.  Credit:  Dr. Dana Graves Lab.

In skin from mice with normal glucose levels (top row), more skin cells (red) migrate into damaged tissue in control mice (left) than in mice lacking FOXO1 (right). But in diabetic mice (bottom row), more skin cells migrate into the wound in animals lacking FOXO1 (right) than in controls (left). Blue marks cell nuclei, and the dotted line delineates the boundary between the epidermis and the dermis. Credit: Dr. Dana Graves Lab.

 

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