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How mesenchymal stem cells speed wound healing in gum tissue

To assist with wound healing, mesenchymal stem cells from the gum tissue secrete extracellular vesicles (labeled red) that contain the anti-inflammatory signaling molecule IL-1RA (labeled green). Photo courtesy the University of Pennsylvania

New insights into how gingival mesenchymal stem cells (GMSCs) in the gums speed wound healing in the mouth may translate into treatments for other wounds for faster healing and reduced scar formation.

Researchers who used a mouse model to explore why oral wounds heal quickly found that GMSCs release small vesicles containing signalling proteins that up-regulate healing processes and control inflammation, according to findings published in Science Translational Medicine (Mar. 14, 2018; 10(432):eaai8542).

“This study represents the convergence of a few different paths we’ve been exploring,” senior author Songtao Shi, DDS, PhD, chair and professor of the University of Pennsylvania School of Dental Medicine’s department of anatomy and cell biology said in a press release. “First, we know as dentists that the healing process is different in the mouth; it is much faster than in the skin. Second, we discovered in 2009 that the gingiva contains mesenchymal stem cells and that they can do a lot of good therapeutically. And, third, we know that mesenchymal stem cells release a lot of proteins. So here we asked: How are the gingival mesenchymal stem cells releasing all of these materials, and are they accelerating wound healing in the mucosal tissues?”

Earlier work from Dr. Shi’s team and others had shown that mesenchymal stem cells perform many of their functions through the release of signalling molecues in extracellular vesicles.

Skin, gum stem cells compared

To understand the difference in the performance of GMSCs and mesenchymal stem cells in the skin, the research team compared the extracellular vesicles they produced. They found that GMSCs contained more proteins overall, including the inflammation-dampening interleukin (IL)-1RA, which blocks a proinflammatory cytokine. IL-1RA is also used as a therapy for rheumatoid arthritis.

Suspecting that a protein known as Fas, which they had shown in earlier research to have a role in immune regulation, might be controlling the release of IL-1RA and other cytokines, the investigators compared levels of Fas and found that GMSCs had more Fas than mesenchymal stem cells in the skin. As well, mice deficient in Fas had reduced IL-1RA and reduced IL-1RA secretion.

Fas was also found to form a protein complex with the proteins Fap-1 and Cav-1, and that complex triggered the release of small extracellular vesicles.

IL-1RA levels and healing speed

An examination of wound tissue showed that levels of Il-1RA were increased in GMSCs around the margins of wounds. Mice that lacked IL-1RA, or in which it had been blocked, took longer to heal wounds to their gums as well. When investigators isolated IL-1RA secreted by GMSCs and injected it into wounds, wound healing significantly accelerated.

These findings may be important to people with diabetes, as the authors found that GMSCs in mice with diabetes were less able to secrete the extracellular vesicles, and their GMSCs secreted less IL-1RA, than GMSCs in healthy mice. When GMSC-secreted extracellular vesicles from healthy mice were introduced into mice with diabetes, the wound healing time of the recipient mice was reduced.

“Our paper is just part of the mechanism of how these stem cells affect wound healing,” lead author Xiaoxing Kou, DDS, PhD said in the release, “but I think we can build on this and use these cells or the extracellular vesicles to target a lot of different diseases, including the delayed wound healing seen in diabetic patients.” Dr. Kou is a stomatologist in the department of orthodontics, Peking University School and Hospital of Stomatology.

Moving forward, Dr. Shi, Dr. Kou and colleagues want to move their work into the clinic.

“We are targeting translational therapies,” said Dr. Shi. “These cells are easy to harvest from the gingiva, and that makes them a beautiful cell for clinical use. We have a lot of work ahead of us, but I can see using these cells to reduce scar formation, improve wound healing, and even treat many inflammatory and autoimmune diseases.”

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