Journal of dentistry · 2025
Regulatory T Cells promote osteogenic differentiation of periodontal ligament stem cells through the Jagged1-Notch2 signaling Axis.
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Yang Nan, Xia Yu, Gao Hui, Wang Chen, Jiang Ying, Song Wei, Yu Ji-Feng, Liang Li
Аннотация
OBJECTIVES: This study aimed to elucidate the role of regulatory T cells (Tregs) in promoting the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) and to investigate the underlying mechanisms involving Notch signaling.
METHOD: Tregs were isolated via fluorescence-activated cell sorting (FACS) and co-cultured with PDLSCs. Osteogenic differentiation was assessed through in vitro assays and in vivo transplantation experiments. Gene expression profiles were quantified using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot analysis. A murine periodontitis model was used to validated therapeutic outcomes, with bone remodeling quantified by micro-CT and histology (H&E, Masson's staining). Immunophenotypic analysis of Jagged1 expression in Tregs and Notch2 receptor localization in PDLSCs were performed using flow cytometry and immunofluorescence microscopy, respectively. The role of immobilized Jagged1 in osteogenic differentiation was further evaluated, while Notch pathway inhibition was achieved via γ-secretase inhibitor DAPT in vitro.
RESULTS: Elevated levels of Th17 cells and Tregs were observed in peripheral blood samples from periodontitis patients, with a significantly increased Th17/Treg ratio (p < 0.01). In vitro, co-culturing Tregs with PDLSCs significantly enhanced PDLSC osteogenesis, as evidenced by increased ALP activity (p < 0.01), elevated expression of osteogenesis-related genes (Runx2 and Osterix; p < 0.01), and enhanced mineralization (Alizarin Red staining) (p < 0.01). In vivo, intravenous infusion of Tregs into a periodontitis mouse model reduced periodontal damage and promoted bone regeneration, as demonstrated by reduced CEJ-ABC distance and increased BV/TV ratio (p < 0.01). Mechanistically, Tregs expressed the Notch ligand Jagged1 and upregulated Notch2 receptor expression in PDLSCs, indicating activation of the Notch signaling pathway. Jagged1 promoted osteogenic differentiation of PDLSCs in a dose- and time-dependent manner. Inhibition of Notch signaling using DAPT reduced Tregs-mediated enhancement of PDLSC osteogenesis (p < 0.05).
CONCLUSION: These findings suggest that Tregs promote PDLSC osteogenic differentiation via Jagged1-Notch2 signaling, highlighting the therapeutic potential of modulating Tregs and Notch signaling for periodontal regeneration and bone tissue engineering.
CLINICAL SIGNIFICANCE: This study provides new insights into the complex interplay between immune modulation and stem cell differentiation, laying the foundation for potential Tregs-based therapeutic strategies for periodontal and bone tissue regeneration.
METHOD: Tregs were isolated via fluorescence-activated cell sorting (FACS) and co-cultured with PDLSCs. Osteogenic differentiation was assessed through in vitro assays and in vivo transplantation experiments. Gene expression profiles were quantified using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot analysis. A murine periodontitis model was used to validated therapeutic outcomes, with bone remodeling quantified by micro-CT and histology (H&E, Masson's staining). Immunophenotypic analysis of Jagged1 expression in Tregs and Notch2 receptor localization in PDLSCs were performed using flow cytometry and immunofluorescence microscopy, respectively. The role of immobilized Jagged1 in osteogenic differentiation was further evaluated, while Notch pathway inhibition was achieved via γ-secretase inhibitor DAPT in vitro.
RESULTS: Elevated levels of Th17 cells and Tregs were observed in peripheral blood samples from periodontitis patients, with a significantly increased Th17/Treg ratio (p < 0.01). In vitro, co-culturing Tregs with PDLSCs significantly enhanced PDLSC osteogenesis, as evidenced by increased ALP activity (p < 0.01), elevated expression of osteogenesis-related genes (Runx2 and Osterix; p < 0.01), and enhanced mineralization (Alizarin Red staining) (p < 0.01). In vivo, intravenous infusion of Tregs into a periodontitis mouse model reduced periodontal damage and promoted bone regeneration, as demonstrated by reduced CEJ-ABC distance and increased BV/TV ratio (p < 0.01). Mechanistically, Tregs expressed the Notch ligand Jagged1 and upregulated Notch2 receptor expression in PDLSCs, indicating activation of the Notch signaling pathway. Jagged1 promoted osteogenic differentiation of PDLSCs in a dose- and time-dependent manner. Inhibition of Notch signaling using DAPT reduced Tregs-mediated enhancement of PDLSC osteogenesis (p < 0.05).
CONCLUSION: These findings suggest that Tregs promote PDLSC osteogenic differentiation via Jagged1-Notch2 signaling, highlighting the therapeutic potential of modulating Tregs and Notch signaling for periodontal regeneration and bone tissue engineering.
CLINICAL SIGNIFICANCE: This study provides new insights into the complex interplay between immune modulation and stem cell differentiation, laying the foundation for potential Tregs-based therapeutic strategies for periodontal and bone tissue regeneration.