Vitamin D and immunomodulation by mesenchymal stem cells

Several studies have demonstrated that oral tissues are rich sources of mesenchymal stem cells (MSCs). The properties of these cells are largely similar to those isolated from bone marrow. An important ability of these cells is the modulation of immune response, which is achieved through secretion of different mediators, as well as by cell-to-cell contact. Fine-tuning of immune response by MSCs is thought to play an important role in different inflammatory diseases. Moreover, application of MSCs for treatment of autoimmune disease and graft rejection are currently introduced into clinical practice. In turn, cytokines, secreted by immune cells, affect immunomodulation activity of adult stem cells by feedback mechanisms. Thus, the interaction between MSCs and immune cells could represent an important mechanism regulating local tissue homeostasis under physiological and pathological conditions. Vitamin D is known to play an important role in bone metabolism and mineral homeostasis. Vitamin D is produced by skin upon exposure to sunlight and is further converted by the liver into 25(OH)D3, which is the main form of this hormone in the blood, and subsequently by the kidney into the biologically active form, 1,25(OH)2D3. Recent studies and our data show that bioactivation of vitamin D might also occur in extrarenal tissues, particularly in dental tissue. Moreover, our preliminary data show that vitamin D influence the response of stem cells derived from dental tissue to bacterial components. The main hypothesis of the present project is that vitamin D influences the interaction between MSCs and immune cells. To answer this question, stem cells will be isolated from different dental tissue, and the effect of vitamin D on their interaction with immune cells will be investigated. Furthermore, the properties of MSCs isolated from healthy individuals will be compared with those isolated from periodontitis patients. This approach will help to clarify possible role of MSCs and vitamin D in progression of periodontitis, which is one of the most common diseases worldwide. It is expected that the results of this project will help to understand how vitamin D influences immunomodulatory properties of MSCs. In addition it will extend existing knowledge on the mechanisms underlying the interaction between MSCs and immune cells and clarify the role of vitamin D in local tissue homeostasis. Furthermore, the project will be also important to justify the use of MSCs isolated from dental origin for tissue regeneration and/or for treatment of immune diseases. Data obtained in the project could be a basis for considering an application of vitamin D in treatment/prophylaxis of inflammatory diseases, particularly periodontitis.

Oral tissues are rich sources of mesenchymal stem cells (MSCs). The properties of these cells are largely similar to those isolated from bone marrow. An important ability of these cells is their modulation of the immune response, which is achieved through the secretion of different mediators, as well as by cell-to-cell contact. Fine-tuning of the immune response by MSCs is thought to play an essential role in various inflammatory diseases. Moreover, the application of MSCs for the treatment of autoimmune disease and graft rejection is currently introduced into clinical practice. The present project showed that the interaction between MSCs and immune cells is complex and multifaceted. The immunomodulatory activity of dental MSCs is low in the resting state and is activated by various inflammatory cytokines. On the one hand, the production of cytokines by immune cells activates the immunomodulatory activity of dental MSCs. On the other hand, activated dental MSCs suppress the activity of immune cells, leading to lower cytokine production. In this project we showed that various inflammatory cytokines activate different immunomodulatory aspects. Thus, we have a complex reciprocal interaction between immune cells and dental MSCs, which is regulated by the local microenvironment. This interaction could be essential in the progression of periodontal disease and dental tissue regeneration. The data of this project have further shown that the reciprocal interaction between immune cells and dental MSCs is affected by vitamin D3 in multiple ways. First, vitamin D3 inhibits the activity of various immune cells and diminishes their production of pro-inflammatory cytokines. Second, vitamin D3 inhibits the immunomodulatory activity of dental MSCs and might even partially abolish their immunosuppressive effects towards immune cells. Third, the local activity of vitamin D3 in dental MSCs is inhibited by inflammatory conditions and regulated by inflammatory cytokines. Thus, on the one hand, vitamin D3 modifies the local microenvironment, and on the other hand, its bioactivity is also modified by this microenvironment. Our data imply that vitamin D3 could be considered as an important factor as adjunctive therapy in periodontitis. However, higher doses of vitamin D3, than current recommended, might be necessary for effective therapy. In addition, the effectiveness of vitamin D3 in clinical applications in dentistry might be enhanced through modification of the local microenvironment, but the optimal conditions have yet to be identified. Nevertheless, our findings open a tremendous perspective for future research focusing on improving the local effects of vitamin D3 in dental tissues.