Abstract
BackgroundTo investigate the odonto-immunomodulatory properties of dental pulp stem cell-derived small extracellular vesicles (DPSCs-sEV), which promote odontogenesis by switching macrophages toward the pro-healing M2 phenotype.MethodsMicroRNA sequencing was carried out for microRNA profiling of DPSCs-sEV. Automated Western blot, qPCR, ELISA, and flow cytometry were performed to identify the functions of microRNA-enriched DPSCs-sEV in macrophages. A luciferase reporter gene assay was carried out to confirm exosomal miR-125a-3p’s direct target gene. DPSCs-sEV-stimulated macrophage-conditioned media were used to promote odontogenesis in DPSCs and explore the mechanism of immune response in DPSCs-SEV-stimulated odontogenesis. DPSCs-sEV were injected into the exposed pulp tissue of rat incisor to investigate the odonto-immunomodulatory properties of DPSCs-sEV in vivo.ResultsDPSCs-sEV switched macrophages to the pro-healing M2 phenotype by inhibiting TLR and NFκΒ signaling. MicroRNA sequencing found 81 microRNAs significantly altered in DPSCS-sEV, with miR-125a-3p showing a 12-fold upregulation. Exosomal miR-125a-3p switched macrophages toward the M2 phenotype via inhibiting NFκΒ and TLR signaling via direct IKBKB targeting. Interestingly, DPSCs-sEV and the encapsulated miR-125a-3p enhanced BMP2 release in macrophages, promoting odontogenesis in DPSCs through BMP2 pathway activation. The rat study confirmed that DPSCs-sEV could be used as ideal biomimetic tools to enhance odontogenesis by switching macrophages toward pro-healing M2 cells.ConclusionsWe firstly defined the odonto-immunomodulatory properties of microRNA-enriched DPSCs-sEV, which could be used as ideal biomimetic tools to enhance odontogenesis by switching macrophages toward the pro-healing M2 phenotype.
Highlights
Maintaining a vital dental pulp has extremely high importance in dentistry [1] and is critical in developing favorable biomaterials facilitating the repair of the injured pulp [2]
We firstly defined the odonto-immunomodulatory properties of microRNA-enriched Dental pulp stem cells (DPSCs)-sEV, which could be used as ideal biomimetic tools to enhance odontogenesis by switching macrophages toward the prohealing M2 phenotype
These findings indicated that DPSCs-sEV-associated macrophage polarization does not induce inflammation, but adequately improves odontogenesis by upregulation of anti-inflammatory cytokines and Bone morphogenetic protein 2 (BMP2), which activates BMP signaling in DPSCs, promoting odontogenic differentiation
Summary
Maintaining a vital dental pulp has extremely high importance in dentistry [1] and is critical in developing favorable biomaterials facilitating the repair of the injured pulp [2]. As exogenous bodies, biomaterials could elicit significant immune reactions, which may play a pivotal role in dental pulp healing and the repair process [3]. Inflammatory cytokines enhance generative dentin formation by odontoblasts, as well as dental pulp stem cell (DPSC) differentiation [4, 5]. The above findings suggest that pulp capping biomaterials would be capable of immunomodulation, regulating immune reactions to promote pulp healing. Macrophages affect the odontogenic differentiation of stem cells as well as dental pulp repair [9, 10]. To investigate the odonto-immunomodulatory properties of dental pulp stem cell-derived small extracellular vesicles (DPSCs-sEV), which promote odontogenesis by switching macrophages toward the pro-healing M2 phenotype
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