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Chitosan hydrogel incorporated with dental pulp stem cell-derived exosomes alleviates periodontitis in mice via a macrophage-dependent mechanism.

ABSTRACT: 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.

SUBMITTER: Shen Z

PROVIDER: S-EPMC7371600 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Chitosan hydrogel incorporated with dental pulp stem cell-derived exosomes alleviates periodontitis in mice via a macrophage-dependent mechanism.

Shen Zongshan Z Kuang Shuhong S Zhang Yong Y Yang Mingmei M Qin Wei W Shi Xuetao X Lin Zhengmei Z

Bioactive materials 20200716 4

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 t ...[more]

PMID: 32743122

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Project description:BackgroundDental pulp stem cells (DPSCs) play a crucial role in dentin-pulp complex regeneration. Further understanding of the mechanism by which DPSCs remain in a quiescent state could contribute to improvements in the dentin-pulp complex and dentinogenesis.MethodsTSC1 conditional knockout (DMP1-Cre+; TSC1f/f, hereafter CKO) mice were generated to increase the activity of mechanistic target of rapamycin complex 1 (mTORC1). H&E staining, immunofluorescence and micro-CT analysis were performed with these CKO mice and littermate controls. In vitro, exosomes were collected from the supernatants of MDPC23 cells with different levels of mTORC1 activity and then characterized by transmission electron microscopy and nanoparticle tracking analysis. DPSCs were cocultured with MDPC23 cells and MDPC23 cell-derived exosomes. Alizarin Red S staining, ALP staining, qRT‒PCR, western blotting analysis and micro-RNA sequencing were performed.ResultsOur study showed that mTORC1 activation in odontoblasts resulted in thicker dentin and higher dentin volume/tooth volume of molars, and it increased the expression levels of the exosome markers CD63 and Alix. In vitro, when DPSCs were cocultured with MDPC23 cells, odontoblastic differentiation was inhibited. However, the inhibition of odontoblastic differentiation was reversed when DPSCs were cocultured with MDPC23 cells with mTORC1 overactivation. To further study the effects of mTORC1 on exosome release from odontoblasts, MDPC23 cells were treated with rapamycin or shRNA-TSC1 to inactivate or activate mTORC1, respectively. The results revealed that exosome release from odontoblasts was negatively correlated with mTORC1 activity. Moreover, exosomes derived from MDPC23 cells with active or inactive mTORC1 inhibited the odontoblastic differentiation of DPSCs at the same concentration. miRNA sequencing analysis of exosomes that were derived from shTSC1-transfected MDPC23 cells, rapamycin-treated MDPC23 cells or nontreated MDPC23 cells revealed that the majority of the miRNAs were similar among these groups. In addition, exosomes derived from odontoblasts inhibited the odontoblastic differentiation of DPSCs, and the inhibitory effect was positively correlated with exosome concentration.ConclusionmTORC1 regulates exosome release from odontoblasts to inhibit the odontoblastic differentiation of DPSCs, but it does not alter exosomal contents. These findings might provide a new understanding of dental pulp complex regeneration.

Dataset Information

Chitosan hydrogel incorporated with dental pulp stem cell-derived exosomes alleviates periodontitis in mice via a macrophage-dependent mechanism.

Publications

Chitosan hydrogel incorporated with dental pulp stem cell-derived exosomes alleviates periodontitis in mice via a macrophage-dependent mechanism.

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