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Insulin-like growth factor binding proteins 7 prevents dental pulp-derived mesenchymal stem cell senescence via metabolic downregulation of p21

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Abstract

Cellular senescence affects the efficacy of mesenchymal stem cells (MSCs)-mediated tissue regeneration. Insulin-like growth factor binding proteins-7 (IGFBP7), as a member of the IGF family, is associated with osteogenic differentiation and the senescence of MSCs, but its exact function and mechanism remain unclear. We found IGFBP7 promoted the osteogenic differentiation and prevented the senescence of dental pulp-derived MSCs (DPSCs), as observed in the gain-of-function and loss-of-function analyses, the senescence-associated marker p21 showed the most pronounced expression changes. We demonstrated that IGFBP7 activated the biological activity of SIRT1 deacetylase via metabolism, resulting in a deacetylation of H3K36ac and a decrease of the binding affinity of H3K36ac to p21 promoter, thereby reducing the transcription of p21, which ultimately prevents DPSCs senescence and promotes tissue regeneration. The activation of the mitochondrial electron transport chain (ETC) by Coenzyme Q10 could rescue the promotion of DPSC senescence induced by the knockdown of IGFBP7, whereas the inhibition of ETC by rotenone attenuated the prevention of DPSC senescence induced by IGFBP7 overexpression. In conclusion, our present results reveal a novel function of IGFBP7 in preventing DPSC senescence via the metabolism-induced deacetylation of H3K36ac and reduction of p21 transcription, suggesting that IGFBP7 is a potential target for promoting tissue regeneration in an aging environment.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82030031, 81991504, 92149301, 82001067), the Chinese Research Unit of Tooth Development and Regeneration, Academy of Medical Sciences (2019-12M-5-031), the Beijing Municipal Science and Technology Commission (Z181100001718208), the Beijing Municipal Education Commission (119207020201), Beijing Advanced Innovation Center for Big Data-based Precision Medicine (PXM2021_014226_000026), the Beijing Municipal Government (Beijing Scholar program PXM2020_014226_000005, PXM2021_014226_000020), Innovation Research Team Project of Beijing Stomatological Hospital, Capital Medical University (CXTD202201), Beijing Municipal Administration of Hospitals’ Youth Program (QML20191504), Scientific Research Common Program of Beijing Municipal Commission of Education (KM202110025009) and Beijing Talents Fund (2018000021469G285). We gratefully acknowledge Beijing Laboratory of Oral Health and Molecular Laboratory for Gene Therapy and Tooth Regeneration. We acknowledge all the laboratory members for their contributions.

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  1. Contributed equally to this work

Authors and Affiliations

  1. Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health, Capital Medical University School of Stomatology, Beijing, 100050, China

    Xiaoyu Li, Liang Feng, Chunmei Zhang, Jinsong Wang, Songlin Wang & Lei Hu

  2. Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China

    Chunmei Zhang, Jinsong Wang, Songlin Wang & Lei Hu

  3. Department of Biochemistry and Molecular Biology, Capital Medical University School of Basic Medicine, Beijing, 100069, China

    Jinsong Wang & Songlin Wang

  4. Laboratory for Oral and General Health Integration and Translation, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China

    Songlin Wang & Lei Hu

  5. Research Unit of Tooth Development and Regeneration, Chinese Academy of Medical Sciences, Beijing, 100700, China

    Songlin Wang & Lei Hu

  6. Department of Prosthodontics, Capital Medical University School of Stomatology, Beijing, 100050, China

    Lei Hu

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  1. Xiaoyu Li
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  3. Chunmei Zhang
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Correspondence to Songlin Wang or Lei Hu.

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Electronic supplementary material

Figure S1. Efficiency of knockdown and overexpression of IGFBP7 in DPSCs.

Figure S2. Osteogenic differentiation of IGFBP7 knockdown DPSCs.

Figure S3. Osteogenic differentiation of IGFBP7 overexpressed DPSCs.

11427_2021_2096_MOESM4_ESM.pdf

Figure S4. The expression of genes related to mitochondrial biogenesis and glycolytic key enzymes in IGFBP7 knockdown DPSCs.

11427_2021_2096_MOESM5_ESM.pdf

Figure S5. The expression of genes related to mitochondrial biogenesis and glycolytic key enzymes in IGFBP7 overexpressed DPSCs.

Figure S6. The expression of genes related to SIRT1-7 in IGFBP7 knockdown or overexpressed DPSCs.

Figure S7. The function of ROT and CoQ10 on DPSCs in normal condition.

11427_2021_2096_MOESM8_ESM.pdf

Figure S8. The function of ROT and CoQ10 on the expression of p21, H3K36ac and SIRT1 in IGFBP7 overexpression and knockdown DPSCs.

Table S1 Gene primers

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Li, X., Feng, L., Zhang, C. et al. Insulin-like growth factor binding proteins 7 prevents dental pulp-derived mesenchymal stem cell senescence via metabolic downregulation of p21. Sci. China Life Sci. 65, 2218–2232 (2022). https://doi.org/10.1007/s11427-021-2096-0

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