Immunosuppressive Polymeric Nanoparticles Targeting Dendritic Cells Alleviate Lupus Disease in Fcgr2b-/- Mice by Mediating Antigen-Specific Immune Tolerance.

Dendritic cells (DCs) are the most potent antigen-presenting cells that have multifaceted functions in the control of immune activation and tolerance. Hyperresponsiveness and altered tolerogenicity of DCs contribute to the development and pathogenesis of system lupus erythematosus (SLE); therefore, DC-targeted therapies aimed at inducing specific immune tolerance have become of great importance for the treatment of SLE. This study developed a new nanoparticle (NP) containing a biodegradable PDMAEMA-PLGA copolymer for target-oriented delivery to DCs in situ. PDMAEMA-PLGA NPs provided sustained drug release and exhibited immunosuppressive activity in FLT3L and GM-CSF-derived bone marrow in conventional DCs (BM-cDCs). PDMAEMA-PLGA NPs improved dexamethasone capability to convert wild-type and Fcgr2b-/- BM-cDCs from an immunogenic to tolerogenic state, and BM-cDCs treated with dexamethasone-incorporated PDMAEMA-PLGA NPs (Dex-NPs) efficiently mediated regulatory T cell (Treg) expansion in vitro. Dex-NP therapy potentially alleviated lupus disease in Fcgr2b-/- mice by mediating Foxp3+ Treg expansion in an antigen-specific manner. Our findings substantiate the superior efficacy of DC-targeted therapy using the PDMAEMA-PLGA NP delivery system and provide further support for clinical development as a potential therapy for SLE. Furthermore, PDMAEMA-PLGA NP may be a versatile platform for DC-targeted therapy to induce antigen-specific immune tolerance to unwanted immune responses that occur in autoimmune disease, allergy, and transplant rejection.

Interleukin 15 participates in Jagged1-induced mineralization in human dental pulp cells.

OBJECTIVES: Crosstalk between Notch and other cell signaling molecules has been implicated to regulate the osteogenic differentiation. Understanding the interaction between Notch and IL15 is essential to reveal molecular mechanism. Thus, the objective of the present study was to investigate whether IL15 participates in the Notch signaling-induced mineral deposition in human dental pulp cells (hDPs). METHODS: hDPs were explanted from dental pulp tissues. To activate Notch signaling, the cells were seeded on Jagged1-immobilized surfaces. The mRNA expression was evaluated using real-time polymerase chain reaction. hDPs were treated with 5-50 ng/mL IL15. Cell viability and proliferation were determined using an MTT assay. Mineral deposition was examined using alizarin red s and Von Kossa staining. In some experiments, the cells were pretreated with a JAK inhibitor prior to stimulation. RESULTS: Jagged1 induced IL15 and IL15RA expression in hDPs. IL15 treatment significantly increased mineral deposition at 14 d and upregulated ALP, OCN, OSX, ANKH, and ENPP1 mRNA expression. IL15-induced mineralization was attenuated by JAK inhibitor pretreatment. Further, JAK inhibitor pretreatment inhibited the effect of Jagged1 on hDP mineral deposition. CONCLUSION: IL15 promoted the osteogenic differentiation in hDPs. Moreover, IL15 participated in the Jagged1-induced mineralization in hDPs.

Differential expression of Notch related genes in dental pulp stem cells and stem cells isolated from apical papilla.

Although dental pulp and apical papilla are originated from neural crest cells, these tissues exhibit distinct characteristics. Notch signaling is one of the known signaling pathways regulating stemness and behaviors of stem cells. The aim of this study was to examine Notch signaling related gene expression profile comparing between coronal pulp tissues and apical pulp complex. Results demonstrated that coronal pulp tissue had higher expression levels of various genes in Notch pathway. However, NOTCH2, MAML2, DTX4, and NEDD4 mRNA levels were significantly lower in coronal pulp tissue than those of apical pulp complex. Furthermore, dental pulp stem cells (DPSCs) and stem cells isolated from apical papilla (SCAPs) were isolated and characterized. These two cell types exhibited similar mesenchymal stem cell surface markers. DPSCs expressed higher mRNA levels of NOTCH3, NOTCH4, DLL1, and HES1. In addition, SCAPs demonstrated higher colony formation and cell proliferation than DPSCs. In summary, cells and tissues from dental pulp and apical papilla exhibited the distinct gene expression profile of Notch related genes. This could be of one the signaling participated in control of DPSCs and SCAPs cells behaviors.