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Periodontitis is caused by host immune-inflammatory response to bacterial insult. A high proportion of pro-inflammatory macrophages to anti-inflammatory macrophages leads to the pathogenesis of periodontitis. As stem cell-derived exosomes can modulate macrophage phenotype, dental pulp stem cell-derived exosomes (DPSC-Exo) can effectively treat periodontitis. In this study, we demonstrated that DPSC-Exo-incorporated chitosan hydrogel (DPSC-Exo/CS) can accelerate the healing of alveolar bone and the periodontal epithelium in mice with periodontitis. Gene Ontology (GO) term enrichment analysis showed that treatment with DPSC-Exo/CS ameliorated periodontal lesion by suppressing periodontal inflammation and modulating the immune response. Specifically, DPSC-Exo/CS facilitated macrophages to convert from a pro-inflammatory phenotype to an anti-inflammatory phenotype in the periodontium of mice with periodontitis, the mechanism of which could be associated with miR-1246 in DPSC-Exo. These results not only shed light on the therapeutic mechanism of DPSC-Exo/CS but also provide the basis for developing an effective therapeutic approach for periodontitis., Graphical abstract Image 1, Highlights • DPSC-Exo/CS accelerates the healing of periodontal tissues in mice with periodontitis. • DPSC-Exo/CS ameliorates periodontitis by modulating the immune response. • The immunomodulatory effects of DPSC-Exo/CS are associated with miR-1246 in DPSC-Exo. • DPSC-Exo/CS is a promising therapy for periodontitis.

Impaired wound healing presents great health risks to patients. While encouraging, the current clinical successes of mesenchymal stromal cell (MSC)-based therapies for tissue repair have been limited. Genetic engineering could endow MSCs with more robust regenerative capacities. Here, we identified that C-C motif chemokine receptor 2 (CCR2) overexpression enhanced the targeted migration and immunoregulatory potential of MSCs in response to C-C motif chemokine ligand 2 (CCL2) in vitro. Intravenously infusion of CCR2-engineered MSCs (MSCsCCR2) exhibited improved homing efficiencies to injured sites and lungs of diabetic mice. Accordingly, MSCCCR2 infusion inhibited monocyte infiltration, reshaped macrophage inflammatory properties, prompted the accumulation of regulatory T cells (Treg cells) in injured sites, and reshaped systemic immune responses via the lung and spleen in mouse diabetic wound models. In summary, CCR2-engineered MSCs restore immunological homeostasis to accelerate diabetic wound healing via their improved homing and immunoregulatory potentials in response to CCL2. Therefore, these findings provide a novel strategy to explore genetically engineered MSCs as tools to facilitate tissue repair in diabetic wounds.

Diabetes-associated periodontitis (DP) aggravates diabetic complications and increases mortality from diabetes. DP is caused by diabetes-enhanced host immune-inflammatory responses to bacterial insult. In this study, we found that persistently elevated CCL2 levels in combination with proinflammatory monocyte infiltration of periodontal tissues were closely related to DP. Moreover, inhibition of CCL2 by oral administration of bindarit reduced alveolar bone loss and increased periodontal epithelial thickness by suppressing periodontal inflammation. Furthermore, bindarit suppressed the infiltration of proinflammatory monocytes and altered the inflammatory properties of macrophages in the diabetic periodontium. This finding provides a basis for the development of an effective therapeutic approach for treating DP.

Background Hyperglycemic micro-environment induced by diabetes could regulate the response of periodontal tissues to pathogenic microorganisms in which disruption of autophagy lysosomal pathway (ALP) may participate. This study aimed to explore the mechanisms underlying how high glucose (HG) regulates ALP in gingival epithelial cells (GECs). Methods Human gingival tissues in healthy group (C), periodontitis group (P), diabetes group (DM), and diabetes + periodontitis group (DP) were collected and were applied to observe the fusion of autophagy and lysosome. Diabetic mouse model with periodontitis was established and RNA-seq was applied to investigate the expression of ALP-associated genes in gingival epithelium. To explore the key role of ATPase transmembrane v0 domain, subunit c (ATP6V0C) in the disruption of ALP by HG, human gingival epithelial cells (HGECs) were cultured in 5.5 mM/25 mM glucose medium for 48 hours and followed by Porphyromonas gingivalis stimulation for 0, 6, and 12 hours. HBLV-h-ATP6V0C was transfected in HGECs that were stimulated by 25 mM HG condition. Results Immunofluorescence double staining exhibited the disruption of ALP in human gingival epithelium in diabetes groups and HGECs under 25 mM glucose condition, accompanied with significantly downregulated lysosomal acidity. RNA-seq of mouse gingival epithelium screened out Atp6v0c. Compared with HGECs in normal culture medium, ATP6V0C expression and LC3-II/I expression ratio were significantly downregulated, with an upregulated expression of P62, IL-1β in HGECs under HG condition. Over-expression of ATP6V0C rescued HG-induced disruption of ALP in HBLV-h-ATP6V0C transfected HGECs, with significantly upregulation of LC3-II/I and downregulation of P62, IL-1β. Conclusion ATP6V0C mediates HG-induced ALP disruption in HGECs, eventually exacerbates periodontal inflammation.