Overexpressed Sirt1 in MSCs Promotes Dentin Formation in Bmi1-Deficient Mice

• Published in: Journal of dental research Vol. 97; no. 12; pp. 1365 - 1373
• Main Authors: Wang, H., Lv, C., Gu, Y., Li, Q., Xie, L., Zhang, H., Miao, D., Sun, W.
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01-11-2018; SAGE PUBLICATIONS, INC
• Subjects: Apoptosis; Cell differentiation; Cell growth; Cell proliferation; Data analysis; Deacetylation; Defects; Dental pulp; Dentin; Dentin sialoprotein; Dentistry; Gene expression; Genes; Laboratories; Mesenchymal stem cells; Mesenchyme; Microscopy; Mineralization; p53 Protein; Proteins; Rodents; SIRT1 protein; Software; Statistical analysis; Stem cell transplantation; Stem cells; Teeth; Therapeutic applications; Transgenic animals; China; dental papilla mesenchymal cells; Sirt1-transgenic mouse; Prx1; deacetylation; mesenchymal stem cells; p53
• ISSN: 0022-0345; 1544-0591
• DOI: 10.1177/0022034518781509

Sirt1 promotes odontoblastic gene expression in human dental pulp cells, whereas the inhibition of Sirt1 downregulates the expression of those genes. To investigate whether the overexpression of Sirt1 in mesenchymal stem cells (MSCs) driven by Prx1 promoter could rescue the dentin formation defects in Bmi1-deficient (Bmi1−/−) mice, we established the MSCs overexpressing Sirt1 in Bmi1 knockout mice (Sirt1TGBmi1−/−). First, we used Prx1-Cre/ROSAnTnG mice to demonstrate that Prx1 linage cells exist mainly in the pulp horns at 4 wk of age. Second, we found that 4-wk-old Sirt1TG mice had increased tooth volume as compared with wild-type (WT) littermates. The expression level of Sirt1 was significantly higher in dental papilla mesenchymal cells of Sirt1TG mice than WT mice. Furthermore, we demonstrated that the tooth mineralization, dental volume, dentin sialoprotein–immunopositive areas, odontoblastic gene expression, and percentage of proliferating BrdU-positive cells were significantly elevated in the Sirt1TG mice and dramatically reduced in the Bmi1–/– mice versus the WT littermates at 4 wk of age. However, the areas of predentin and the percentage of TUNEL-positive apoptotic cells were significantly reduced in the Sirt1TG mice but dramatically increased in the Bmi1−/− mice as compared with the WT littermates. All these parameters were rescued in the Sirt1TGBmi1−/− mice versus the Bmi1−/− mice. Finally, by using dental papilla mesenchymal cells, we found that the overexpression of Sirt1 rescued the reduced cell proliferation and differentiation and increased the cell apoptosis caused by Bmi1 deficiency, which was associated with increased p53 deacetylation. Therefore, this study indicates that Sirt1 is a potential therapeutic target for promoting dentin formation in an anabolic approach to the treatment of dental developmental defects.