Periodontal Stem Cells Synthesize Maresin Conjugate in Tissue Regeneration 3

Abstract

Periodontal disease is a significant public health problem worldwide. Excess unresolved chronic inflammation destroys the periodontal tissues that surround and support the teeth, and efforts to control inflammation by removal of bacterial deposits on the teeth have limited long-term impact. Likewise, procedures aimed at regeneration of the periodontal tissues have shown limited success. Recent advances in stem cell research have shown promising novel prospects for the use of periodontal ligament stem cells (PDLSCs) in tissue regeneration; however, control of inflammation remains a barrier. Human PDLSCs have been shown to release specialized proresolving lipid mediators (SPMs) that modulate the immune response and promote resolution of inflammation, tissue repair, and regeneration. Studies on stem cell biology in periodontology have also been limited by the lack of a good large animal model. Herein, we describe PDLSC biology of the Yorkshire pig (pPDLSCs). pPDLSCs were isolated and characterized. Using lipid mediator profiling, we demonstrate for the first time that pPDLSCs biosynthesize cysteinyl-containing SPMs (cys-SPMs), specifically, maresin conjugates in tissue regeneration 3 (MCTR3) and its authentication using liquid chromatography/tandem mass spectrometry. The exogenous addition of the n-3 precursor docosahexaenoic acid enhances MCTR3 biosynthesis. Using immunocytochemistry, we show that pPDLSCs express 4 of the SPM biosynthetic pathway enzymes necessary for SPM biosynthesis, including 5-lipoxygenase, 12-lipoxygenase, and 15-lipoxygenase-1. In addition, we identified and quantified the cytokine/chemokine profile of pPDLSCs using a 13-plex immunology multiplex assay and found that the pretreatment of pPDLSCs with MCTR3 in an inflammatory environment reduced the production of acute and chronic proinflammatory cytokines/chemokines. Together, these results suggest that enhancing resolution of inflammation pathways and mediators may be a possible key early event in predictable periodontal regeneration.