image: Stem cells in a pro-resolving environment with maresin and resolvin; image view more
Credit: Emmanuel Albuquerque de Souza/USP
Maresin and resolvin, produced by the body from omega-3 fatty acids, can help repair tissue damaged by periodontal disease. A recent study shows that even in the presence of inflammation they stimulate periodontal ligament stem cells. The periodontal ligament is one of the structures lost in severe cases of the disease.
The study was part of the PhD research of Emmanuel Albuquerque de Souza at the University of São Paulo's Dental School (FO-USP) in Brazil and was conducted at the Forsyth Institute, an affiliate of the Harvard School of Dental Medicine in the United States, with a scholarship from FAPESP (São Paulo Research Foundation ).
Local inflammation is one of the most challenging aspects of the treatment of periodontal disease. "It destroys the tissues that maintain and secure the teeth in the mouth, and although treatment with stem cells stimulates regeneration of these structures in studies performed in vitro and in experimental animals, it doesn't work so well in humans because of inflammation," Souza said.
Forsyth and FO-USP have long studied the mechanisms that lead to a resolution of inflammation in the periodontium. One of the focuses for the partnership is what is called pro-resolving lipid mediators, such as maresin and resolvin. "These molecules come into play in the second stage of the inflammatory process, referred to nowadays as the resolution stage, but some people apparently don't produce enough of them, while in other cases their functions appear to be altered in some way," Souza said.
Stimulating the release of these mediators could be a way to improve the success rate of so-called regenerative therapy. "The study shows for the first time that these two mediators enhance stem cell regenerative capacity even in the presence of inflammation," said Marinella Holzhausen Caldeira, a professor in FO-USP's Department of Periodontics and Souza's thesis advisor in Brazil.
Pro-inflammatory versus pro-resolving environments
Based on previous research demonstrating the action of maresin and resolvin in periodontal regeneration, the group created two in vitro environments for stem cells, one representing inflamed tissue full of pro-inflammatory cytokines, and the other simulating the inflammation resolution stage.
"We found that pro-inflammation reduced stem cell activity, while the presence of maresin and resolvin increased their capacity to proliferate, migrate and rapidly acquire the functions of cells in the lost tissue," Souza said.
"When these stem cells are stimulated, they can acquire properties similar to those of periodontal cementoblasts, fibroblasts, and osteoblasts," Caldeira said.
The finding shows the importance of creating a favorable environment for stem cells to function properly. The next step is understanding how to use maresin and resolvin therapeutically. "We don't know how much we can alter the organism's capacity to synthesize these mediators," Souza said.
One possibility could be to use their precursor, omega-3, via supplementation. "Recent clinical studies have shown that supplementation can have a highly positive effect when combined with basic periodontal therapy, which involves removal of the biofilm that accumulates in the tissue," Caldeira said. The benefits are seen mainly in patients with diabetes or metabolic syndrome, which point to an altered inflammatory profile (read more at: agencia.fapesp.br/34357).
Another possibility could be to treat stem cells with maresin and resolvin before using them in regenerative therapy in order to make the treatment more effective.
The future of the fight against inflammation Although the discovery comes from dentistry, it may pave the way to advances in the treatment of other conditions. "Explaining how these mediators act on the regeneration process means explaining how the organism recovers from an inflammatory disease," Souza said. This is resolution pharmacology, a new line of research that aims to revolutionize the current approach to anti-inflammatory medication.
Recent research has shown that inflammation occurs in two stages. The first involves the release of pro-inflammatory substances as part of the organism's defenses against attack. Next, enzymes are activated to produce a change in various cell phenotypes and the resolution stage begins.
For example, macrophages (one type of immune system cell) that produce many inflammatory cytokines, such as tumor necrosis factor, begin to secrete pro-resolving mediators that clear up the mess made by the inflammation. "The phagocytosis performed by macrophages is important to defend us against bacteria and other microorganisms, but leaves behind a kind of inflammatory refuse that has harmful effects on the organism," Souza said.
The changes driven by pro-resolving mediators lead macrophages and other immune cells to perform this cleansing process and secrete fewer toxins. Similar benefits also appear to come from stem cells, which restore what was lost to inflammation. This is a different view from the use of classic anti-inflammatory drugs to interrupt or block the inflammatory response. "In resolution pharmacology, you don't prescribe a drug to block inflammation. What you want is to stimulate the beneficial inflammatory stage, which is the resolution stage," Souza said.
The approach appears to offer advantages. "Currently we don't have specifically pro-resolving drugs, but this research will lead to the development of alternatives that will overlap with existing anti-inflammatory medications, which have various limitations and adverse side-effects," Caldeira said.
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About São Paulo Research Foundation (FAPESP)
The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at http://www.fapesp.br/en and visit FAPESP news agency at http://www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe.
Journal
Frontiers in Immunology