Development of a novel therapeutic approach for periodontitis that utilizes GMSCs-derived exosome through induction of M2 macrophage

Abstract

Periodontitis is one of the most common osteolytic inflammatory diseases in humans. Formation of a periodontal bacteria-associated biofilm is thought to be a trigger for the development of periodontitis, but it is not believed to be sufficient by itself to sustain the disease, as compromise of the host immune response is critical for inflammatory tissue breakdown and disease progression. Macrophages play an important role in the immune response both during the initiation and resolution of the inflammation. Macrophages are broadly classified into two phenotypes, pro-inflammatory M1 and wound-healing M2 cells. Since M2 macrophages contribute to the tissue-remodeling process, effective M2 macrophage induction would provide a favorable environment for resolution of the inflammation and tissue regeneration.

Mesenchymal stem cell (MSCs) have been applied for the purpose of inducing tissue regeneration and treating autoimmune disorders. Specifically, MSC-derived exosomes have attracted much attention for cell-free MSC therapy, because of their ability to transport vesicular cargo molecules, including growth factors and regulatory miRNAs, which mediate cell-to-cell communication. As compared with other somatic MSCs, gingival tissue-derived MSCs (GMSCs) have the unique capacity for pronounced immunoregulation and secrete large amount of exosomes. Recent studies have indicated that appropriate preconditioning of MSCs with disease-related stimuli can optimize the contents of the exosomes to efficiently support the repair of specific diseases.

In this review, we report the therapeutic effects of TNF-α-preconditioned-GMSC-derived exosomes on periodontal disease and discuss the underlying molecular mechanisms. Our study revealed that TNF-α-enhanced exosomal CD73 expression leading to anti-inflammatory M2 macrophage polarization and exosomal miR-1260b is an important negative regulator of osteoclastogenesis. Accordingly, our findings may pave the way for the development of a novel therapeutic strategy for patients with periodontitis.