Immunomodulatory Properties of PDLSC and Relevance to Periodontal Regeneration

Curr Oral Health Rep (2015) 2:245–251 DOI 10.1007/s40496-015-0062-y STEM-CELL BIOLOGY FOR TOOTH AND PERIODONTAL REGENERATION (M BARTOLD, SECTION EDITOR) Immunomodulatory Properties of PDLSC and Relevance to Periodontal Regeneration Naohisa Wada 1 & Atsushi Tomokiyo 2 & Stan Gronthos 3,4 & P. Mark Bartold 5 Published online: 10 September 2015 # Springer International Publishing AG 2015 Abstract Periodontitis, a major chronic inflammatory disease of dental tissue, causes periodontal tissue destruction and alveolar bone resorption. When large amounts of alveolar bone are lost, it is very difficult to regenerate the bone using conventional treatments. Periodontal ligament stem cells (PDLSCs) have attracted much attention as potential cell sources for alternative periodontitis regenerative treatment because of their capacity for self-renewal and multipotency. Recently, PDLSCs were found to possess immunomodulatory properties. PDLSCs lack the expression of immune costimulating factors and suppress immune cell proliferation following stimulation with mitogens or in mixed allogeneic This article is part of the Topical Collection on Stem-Cell Biology for Tooth and Periodontal Regeneration * Naohisa Wada Atsushi Tomokiyo Stan Gronthos P. Mark Bartold 1 Division of General Dentistry, Kyushu University Hospital, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan 2 Department of Endodontology and Operative Dentistry, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan 3 Mesenchymal Stem Cell Laboratory, School of Medicine, University of Adelaide, Adelaide, SA, Australia 4 South Australian Health and Medical Research Institute, Adelaide, SA, Australia 5 School of Dentistry, Colgate Australian Clinical Dental Research Centre, University of Adelaide, Adelaide, SA, Australia lymphocyte reactions. Because of these characteristics, the anti-inflammatory effects of PDLSCs and the establishment of allogeneic PDLSC transplantation therapies have been well studied. The aim of this review is to provide an assessment of the latest findings on the immunomodulatory properties of PDLSCs and their potential clinical application for periodontal tissue regeneration. Keywords Periodontal regeneration . Periodontal ligament stem cells . Immunomodulatory property . Allogeneic cell transplantation . Transplant rejection . Autoimmune disease Introduction Periodontitis is a chronic inflammatory disease of the periodontal tissue. Periodontitis is caused by bacterial infection, resulting in an inflammatory reaction which leads to the destruction of periodontal tissue, including the periodontal ligament and alveolar bone and, in severe cases, tooth loss. The main approach for the treatment of periodontitis is the removal of dental plaque, which is composed of bacteria. More recently, regenerative treatments for damaged or destroyed periodontal tissue have achieved great progress through the use of barrier membranes, enamel matrix derivative, and recombinant proteins; these have become the mainstay of periodontal treatment [1–4]. However, the efficacy of all these approaches has been limited, because periodontal tissue regeneration is dependent on the presence of the recruitment and differentiation of local stem cells at the site of the damaged tissue. Thus, the development of alternative therapies using dental stem cell transplantation has been investigated as an approach to more efficiently regenerate damaged periodontal tissue. Given that periodontal tissue destruction occurs following bacterial infection and inflammation, the delivery of an 246 exogenous cell source to site of damaged periodontal tissue may be more effective at inducing regeneration, while also exhibiting anti-inflammatory and immunosuppressive properties. In 2000, Gronthos et al. first reported the isolation of dental pulp stem cells (DPSCs) from human dental pulp tissue as dental tissue mesenchymal stem cells (MSCs) [5]. Later, in 2004, periodontal ligament stem cells (PDLSCs) were isolated from human periodontal ligament [6]. Interestingly, although PDLSCs possessed the capacity for self-renewal and multipotential differentiation into osteogenic, adipogenic, and chondrogenic lineages in vitro similar to bone marrow MSCs (BMSCs) and DPSCs, they exhibited their own unique potential in vivo in contrast to other tissue-derived MSCs. When BMSCs, DPSCs, or PDLSCs were subcutaneously transplanted into the dorsal surfaces of immunocompromised mice with hydroxyapatite–tricalcium phosphate ceramic particles as a carrier, BMSCs formed bone-like tissue with bone marrow, DPSCs formed dentin/pulp complex-like tissue, and PDLSCs formed a cementum-like tissue layer with condensed collagen fibers like Sharpey’s fibers, which resembled PDL structures. These observations indicate that different MSClike populations regenerate their tissue of origin in vivo, presumably based on epigenetic memory. Therefore, PDLSCs are an ideal cell source for the regeneration of periodontal tissue compared with MSCs derived from other dental or non-dental tissues. PDLSCs have been reported to possess immunomodulatory properties similar to BMSCs [7••]. This property could be a valuable advantage for cell transplantation therapies as the inflammatory condition in periodontitis inhibits the natural repair processes involving local cells, including stem, progenitor, and mature cells. Chronic periodontitis represents an inflammatory response in the periodontal tissues, which is elicited by bacteria in dental plaque. The early/stable lesion of chronic periodontitis is dominated by T cells and macrophages, which are mediated by T-helper 1 (Th1) cytokines, including interleukin (IL)-1 and interferon (IFN)-γ, while the advanced/ progressive lesion of chronic periodontitis is dominated by B cells and plasma cells, which are dependent on Th2 cytokines, including IL-4 [53]. This inflammation leads to alveolar bone loss caused by excessive activation of osteoclasts [54]. When alveolar bone is extensively resorbed, it is difficult to regenerate bone volume to normal levels owing to quantitative limitations and reduced regenerative capacity caused by inflammation. Thus, to effectively regenerate damaged periodontal tissue, including alveolar bone, the ideal therapy must include both regenerative and anti-inflammatory/immunosuppressive approaches. In this review, we describe the potential of PDLSCs as a cell source for periodontal tissue engineering, with a focus on their immunomodulatory properties. Curr Oral Health Rep (2015) 2:245–251 Immunomodulatory Properties of MSCs In recent decades, MSCs have been widely studied as potential cell therapy agents for transplant rejection and immunemediated diseases because of their immunomodulatory properties, as demonstrated in numerous pre-clinical animal studies and in human clinical trials. MSCs express very low levels of (...truncated)