Human Bone Marrow Mesenchymal Stem Cell-derived Extracellular Vesicles Restore Th17/Treg Homeostasis in Periodontitis via miR-1246

Abstract

Abstract T-cell-mediated immunity is crucial in the immunopathology of periodontitis. The restoration of the equilibrium between the T helper cell 17 (Th17) and regulatory T cell (Treg) subsetsby extrcellular vesicles (EVs) obtained from human bone marrow stem cells (hBMSCs) promotes new bone formation and suppresses inflammation. Uncovering the functions of hBMSC-derived EVs in the immune microenvironment of periodontal tissue and their underlying regulatory mechanisms may shed new light on the development of a potential cell-free immunotherapy for periodontal regeneration. Here we report that The Th17/Treg ratio was elevated in peripheral blood from periodontitis patients. Furthermore,we found that hBMSC-derived EVs could reduce the Th17/Treg ratio in CD4+ T cells from periodontitis patients in vitro and ameliorated experimental periodontitis in mice. Additionally, miRNA sequencing was used to investigate the differentially expressed miRNAs and target genes in EVs from hBMSCs stimulated with P. gingivalis LPS. Our findings indicate that EV-miR-1246 is highly effective at down-regulating the ratio of Th17/Treg in vitro. Mechanistically, EV-miR-1246 suppressed angiotensin-converting enzyme 2 (ACE2) expression and increased the p-Yes-associated protein (YAP)1/YAP1 ratio in CD4+ T cells. Our results indicate that hBMSC-derived EVs improve periodontitis by miR-1246, consequently downregulating Th17/Treg ratio, and represent a promising therapeutic target for precision treatment in periodontitis.