Researchers have uncovered the mechanism that causes wounds to heal more slowly in diabetics, putting them at increased risk of infection and other serious complications. They say their findings could offer a new approach to the disease.
Nano-sized messenger particles that are naturally produced by cells, exosomes are responsible for cell-to-cell communication. They deliver ‘cargo’ that includes proteins, lipids and genetic material, to recipient cells, effectively altering the biological response of the cell.
Exosomes have been associated with immune and inflammatory responses in the body. Now, a new study led by researchers from the University of Pittsburgh has examined the role of exosomes in diabetics, whose wounds tend to heal more slowly and progress more quickly, increasing the risk of infections and other serious complications.
“In patients with diabetes, wound healing is impaired because of excess inflammation,” said Chandan Sen, one of the study’s corresponding authors. “Left untreated, these non-healing, or chronic, wounds can lead to limb amputations. More than 100,000 diabetes-related amputations occur in the US each year, but by understanding more about wound healing and developing new therapies, our goal is to bring this number down.”
The researchers collected fluid from negative pressure bandages placed on the chronic wounds of 22 diabetic and 15 non-diabetic patients. Negative pressure wound therapy (NPWT) promotes wound closure by applying sub-atmospheric pressure to draw out fluid and infection. A special bandage is sealed over the wound and attached to a gentle vacuum pump.
“These bandages would normally be thrown in the trash can, but wound fluid is actually a very valuable sample that reflects what’s going on throughout the wound,” said Sen. “For example, if the wound is infected, the fluid will carry traces of that infection.”
The researchers analyzed the fluid and isolated exosomes produced by keratinocytes, the cells essential to skin repair. Normally, when the cargo-carrying exosomes are released from cells, they’re taken up by macrophages, immune cells that coordinate wound healing.
They found that not only did the exosomes in diabetics – which they called “diaexosomes” – carry different cargo, but the number of diaexosomes was much lower in the wound fluid of diabetics than the number of exosomes in non-diabetic wound fluid, and macrophages took up far fewer exosomes than diabexosomes.
When non-diabetic macrophages were incubated with exosomes, they produced factors to resolve inflammation, indicating that they’d received the correct ‘wound healing’ signal from the exosome. However, when the experiment was repeated using diaexosomes, the macrophages instead produced pro-inflammatory factors.
“If signals contained within exosomes are correct, the macrophage knows how to resolve inflammation in the wound,” Sen said. “In diabetes, the crosstalk between keratinocytes and macrophages is compromised, so macrophages keep driving inflammation and the wound can’t heal.”
The researchers say their findings provide critical insights into a major complication of diabetes and could offer a new approach to the disease.
“Diaexosomes drive deviation from the healing cascade, so that resolution of inflammation is compromised,” said Sen. “And this isn’t just limited to wounds. Because exosomes are responsible for many functions in the body, diaexosomes could play a role in other diabetic complications. This study opens a new line of thinking.”
The researchers are now investigating how they can target diaexosomes to improve wound healing in diabetics. One way, say the researchers, would be to undo the chemical modifications that occur in diaexosomes. Another would be isolate diabetic exosomes and load them with missing ‘cargo’ before infusing them back into the wound tissue.
The study was published in the journal NanoToday.
Source: University of Pittsburgh via EurekAlert!
