mTORC1 promotes mineralization via p53 pathway

Luo, Xinghong; Yin, Jingyao; Miao, Shenghong; Feng, Weiqing; Ning, Tingting; Xu, Shuaimei; Huang, Shijiang; Zhang, Sheng; Liao, Yunjun; Hao, Chunbo; Wu, Buling; Ma, Dandan

doi:10.1096/fj.202002016r

Cited by 4 publications

(12 citation statements)

References 43 publications

(49 reference statements)

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“…mTORC1 is essential for the osteo/odontoblastic differentiation of dental stem cells [ 11 – 13 ]. In our recent study, we confirmed that mTORC1 promoted mineralized matrix secretion by odontoblasts via the p53 signaling pathway [ 14 ]. Additionally, we found that the expression levels of cluster of differentiation 63 (CD63) and apoptosis-linked gene 2-interacting protein (Alix) changed with changes in mTORC1 activity and that predentin was thicker in molars in 6-month-old mice with activated mTORC1.…”

Section: Introductionmentioning

confidence: 57%

Odontoblasts release exosomes to regulate the odontoblastic differentiation of dental pulp stem cells

et al. 2023

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Background Dental 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. Methods TSC1 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. Results Our 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. Conclusion mTORC1 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.

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Section: Introductionmentioning

confidence: 57%

Odontoblasts release exosomes to regulate the odontoblastic differentiation of dental pulp stem cells

et al. 2023

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“…Recent studies on mTORC1 in tooth germs have been limited to tooth development. 46 For instance, studies have shown that inhibition of mTORC1 causes proliferation defects and excessive cell death, resulting in facial growth defects and wrinkles. 27 What's more, mTORC1 inhibition disrupts enamel cell adhesion, proliferation, and differentiation, leading to defective tooth formation and malformations.…”

Section: Discussionmentioning

confidence: 99%

mTORC1 signaling pathway regulates tooth repair

Liu

Zhou

et al. 2023

Int J Oral Sci

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Tooth germ injury can lead to abnormal tooth development and even tooth loss, affecting various aspects of the stomatognathic system including form, function, and appearance. However, the research about tooth germ injury model on cellular and molecule mechanism of tooth germ repair is still very limited. Therefore, it is of great importance for the prevention and treatment of tooth germ injury to study the important mechanism of tooth germ repair by a tooth germ injury model. Here, we constructed a Tg(dlx2b:Dendra2-NTR) transgenic line that labeled tooth germ specifically. Taking advantage of the NTR/Mtz system, the dlx2b+ tooth germ cells were depleted by Mtz effectively. The process of tooth germ repair was evaluated by antibody staining, in situ hybridization, EdU staining and alizarin red staining. The severely injured tooth germ was repaired in several days after Mtz treatment was stopped. In the early stage of tooth germ repair, the expression of phosphorylated 4E-BP1 was increased, indicating that mTORC1 is activated. Inhibition of mTORC1 signaling in vitro or knockdown of mTORC1 signaling in vivo could inhibit the repair of injured tooth germ. Normally, mouse incisors were repaired after damage, but inhibition/promotion of mTORC1 signaling inhibited/promoted this repair progress. Overall, we are the first to construct a stable and repeatable repair model of severe tooth germ injury, and our results reveal that mTORC1 signaling plays a crucial role during tooth germ repair, providing a potential target for clinical treatment of tooth germ injury.

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“…A previous study by our team indicated that mTOR pathway activation significantly enhanced dentin formation. 27 In this study, we conducted further RNA sequencing to investigate the potential involvement of miR-3074-3p in the odontogenic differentiation of hDPSCs. MiR-3074, first reported in 2015, 35 was mainly involved in tumor development, cell metabolism, and tissue repair.…”

Section: Discussionmentioning

confidence: 99%

“… 25 , 26 Our previous study has demonstrated the involvement of the mTOR signaling pathway in regulating the mineralization process of odontoblast cells. 27 This finding suggested that there might be molecular pathways involved in the regulation of odontogenesis under the activation of the mTOR pathway.…”

Section: Introductionmentioning

confidence: 97%

Enhanced effects of antagomiR-3074-3p-conjugated PEI-AuNPs on the odontogenic differentiation by targeting FKBP9

et al. 2023

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The odontogenic differentiation of dental pulp stem cells (DPSCs), which is vital for tooth regeneration, was regulated by various functional molecules. In recent years, a growing body of research has shown that miRNAs play a crucial role in the odontogenic differentiation of human dental pulp stem cells (hDPSCs). However, the mechanisms by which miRNAs regulated odontogenic differentiation of hDPSCs remained unclear, and the application of miRNAs in reparative dentin formation in vivo was also rare. In this study, we first discovered that miR-3074-3p had an inhibitory effect on odontogenic differentiation of hDPSCs and antagomiR-3074-3p-conjugated PEI-AuNPs effectively promoted odontogenic differentiation of hDPSCs in vitro. AntagomiR-3074-3p-conjugated PEI-AuNPs was further applied to the rat pulp-capping model and showed the increased formation of restorative dentin. In addition, the results of lentivirus transfection in vitro suggested that FKBP9 acted as the key target of miR-3074-3p in regulating the odontogenic differentiation of hDPSCs. These findings might provide a new strategy and candidate target for dentin restoration and tooth regeneration.

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mTORC1 promotes mineralization via p53 pathway

Cited by 4 publications

References 43 publications

Odontoblasts release exosomes to regulate the odontoblastic differentiation of dental pulp stem cells

Odontoblasts release exosomes to regulate the odontoblastic differentiation of dental pulp stem cells

mTORC1 signaling pathway regulates tooth repair

Enhanced effects of antagomiR-3074-3p-conjugated PEI-AuNPs on the odontogenic differentiation by targeting FKBP9

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