MicroRNA-enriched small extracellular vesicles possess odonto-immunomodulatory properties for modulating the immune response of macrophages and promoting odontogenesis

Stem Cell Research & Therapy

Yaoyin Li¹  Jianmao Zheng¹  Zhishan Li¹  Xiaoli Hu¹  Xi Wei¹  Junqi Ling¹  Yingqun Zhong¹  Yuanyuan Kong² 

[1] Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University;Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Department of Endodontics, Stomatology Hospital of Guangzhou Medical University;

关键词: Odonto-immunomodulation;    Small extracellular vesicles;    MicroRNAs;    Odontogenesis;    Macrophages;    Dental pulp stem cells;   

DOI  :  10.1186/s13287-020-02039-1

来源: DOAJ

【 摘 要 】

Abstract Background 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. Methods MicroRNA 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. Results DPSCs-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. Conclusions We 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.

【 授权许可】

Unknown