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TGF?? induces periodontal ligament stem cell senescence through increase of ROS production.

ABSTRACT: Periodontal ligament stem cells (PDLSCs) are vital for the regeneration of periodontal tissue. Transforming growth factor (TGF) ?1, a potent stimulator of tissue regeneration, is extensive and abundant in the bone matrix. However, the effect of TGF??1 in periodontal differentiation remains to be elucidated. The present study aimed to evaluate the effect of TGF??1 on human PDLSCs. PDLSCs were isolated using CD146 microbeads, and characterized by flow cytometry. The present study demonstrated that treatment with TGF??1 induced PDLSC senescence, characterized by increases in senescence?associated beta?galactosidase activity and elevation of both p16 and p21 expression. Furthermore, TGF??1 treatment demonstrated the capacity to induce the production of reactive oxygen species (ROS). Of note, addition of a ROS scavenger successfully rescued the TGF??1?induced PDLSC senescence. Thus, the present results indicated that TGF??1 may serve a vital role in PDLSC senescence, and thus represent a potential target involved in the fabrication and formation of hard tissue for clinical treatment.

SUBMITTER: Fan C

PROVIDER: S-EPMC6755147 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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TGF‑β induces periodontal ligament stem cell senescence through increase of ROS production.

Fan Chun C Ji Qiuxia Q Zhang Chunyang C Xu Shuo S Sun Hui H Li Zhiyuan Z

Molecular medicine reports 20190809 4

Periodontal ligament stem cells (PDLSCs) are vital for the regeneration of periodontal tissue. Transforming growth factor (TGF) β1, a potent stimulator of tissue regeneration, is extensive and abundant in the bone matrix. However, the effect of TGF‑β1 in periodontal differentiation remains to be elucidated. The present study aimed to evaluate the effect of TGF‑β1 on human PDLSCs. PDLSCs were isolated using CD146 microbeads, and characterized by flow cytometry. The present study demonstrated that ...[more]

PMID: 31432132

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Project description:BACKGROUND: Periodontal ligament mesenchymal stem cells (PDLSCs) are a promising cell resource for cell-based regenerative medicine in dentistry. PDLSCs inevitably acquire a senescent phenotype after prolonged in vitro expansion, and the key regulators of cells during replicative senescence remain unclear.METHODS: We cultured periodontal ligament stem cells to passages 4, 10 and 20 (P4, P10, P20). The senescent phenotypes, proliferation and migration ability of PDLSCs (P4, P10, P20) were detected, and non-targeted metabonomic sequencing was performed. We treated PDLSCs with AICAR and detected the expression of FOXO1, FOXO3a, FOXO6 and AMPK phosphorylation (p-AMPK) levels of replicating senescent PDLSCs to explore the correlation between the metabolic changes and the AMPK pathway.RESULTS: Immunofluorescence staining of γ-H2AX, β-galactosidase staining, cell scratch test and qPCR were performed to confirm the occurrence of replicative senescence in PDLSCs during passaging. Three groups of cells at passage 4 (P4), passage 10 (P10) and passage 20 (P20) were collected for non-targeted metabolomics analysis. Metabonomic sequencing showed that the metabolism of replicative senescence in PDLSCs varied significantly. In particular, the content of fatty acid metabolites decreased with senescence, including capric acid, stearic acid, myristic acid and dodecanoic acid. KEGG pathway analysis showed that the AMPK signaling pathway was closely related to AMP levels. The AMP:ATP ratio increased in senescent PDLSCs; however, the levels of p-AMPK and the profile of FOXO1 and FOXO3a, which are downstream of the AMPK signaling pathway, decreased with senescence. We treated PDLSCs with AICAR, an activator of the AMPK pathway, and the phosphorylated AMPK level at P20 PDLSCs was partially restored. CONCLUSION: In summary, our study suggests that the metabolic process of PDLSCs is active in the early stage of senescence, prefers to consume fatty acids, and is attenuated in the later stages of senescence. AMP accumulates in replicative senescent PDLSCs; however, the sensitivity of AMPK phosphorylation sites is impaired, causing senescent PDLSCs to fail to respond to changes in energy metabolism. Our findings provide a new basis for the clinical application of periodontal ligament stem cells.

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TGF?? induces periodontal ligament stem cell senescence through increase of ROS production.

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TGF‑β induces periodontal ligament stem cell senescence through increase of ROS production.

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