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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References
Bach, L.A. (2018a). IGF-binding proteins. J Mol Endocrinol 61, T11–T28.
Bach, L.A. (2018b). What happened to the IGF binding proteins? Endocrinology 159, 570–578.
Baxter, R.C. (2014). IGF binding proteins in cancer: mechanistic and clinical insights. Nat Rev Cancer 14, 329–341.
Ben-Porath, I., and Weinberg, R.A. (2005). The signals and pathways activating cellular senescence. Int J Biochem Cell Biol 37, 961–976.
Bosch-Presegué, L., and Vaquero, A. (2015). Sirtuin-dependent epigenetic regulation in the maintenance of genome integrity. FEBS J 282, 1745–1767.
Cao, Y., Liu, Z., Xie, Y., Hu, J., Wang, H., Fan, Z., Zhang, C., Wang, J., Wu, C.T., and Wang, S. (2015). Adenovirus-mediated transfer of hepatocyte growth factor gene to human dental pulp stem cells under good manufacturing practice improves their potential for periodontal regeneration in swine. Stem Cell Res Ther 6, 249.
Carrico, C., Meyer, J.G., He, W., Gibson, B.W., and Verdin, E. (2018). The mitochondrial acylome emerges: proteomics, regulation by sirtuins, and metabolic and disease implications. Cell Metab 27, 497–512.
Chen, Y., Cui, T., Knösel, T., Yang, L., Zöller, K., and Petersen, I. (2011). IGFBP7 is a p53 target gene inactivated in human lung cancer by DNA hypermethylation. Lung Cancer 73, 38–44.
Chen, Z., Li, L., Wu, W., Liu, Z., Huang, Y., Yang, L., Luo, Q., Chen, J., Hou, Y., and Song, G. (2020). Exercise protects proliferative muscle satellite cells against exhaustion via the Igfbp7-Akt-mTOR axis. Theranostics 10, 6448–6466.
Di Micco, R., Krizhanovsky, V., Baker, D., and d’Adda di Fagagna, F. (2021). Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat Rev Mol Cell Biol 22, 75–95.
Evdokimova, V., Tognon, C.E., Benatar, T., Yang, W., Krutikov, K., Pollak, M., Sorensen, P.H.B., and Seth, A. (2012). IGFBP7 binds to the IGF-1 receptor and blocks its activation by insulin-like growth factors. Sci Signal 5, ra92.
Feng, X., Feng, G., Xing, J., Shen, B., Tan, W., Huang, D., Lu, X., Tao, T., Zhang, J., Li, L., et al. (2014). Repeated lipopolysaccharide stimulation promotes cellular senescence in human dental pulp stem cells (DPSCs). Cell Tissue Res 356, 369–380.
Folmes, C.D.L., Dzeja, P.P., Nelson, T.J., and Terzic, A. (2012). Metabolic plasticity in stem cell homeostasis and differentiation. Cell Stem Cell 11, 596–606.
Goodell, M.A., and Rando, T.A. (2015). Stem cells and healthy aging. Science 350, 1199–1204.
Haigis, M.C., Deng, C.X., Finley, L.W.S., Kim, H.S., and Gius, D. (2012). SIRT3 is a mitochondrial tumor suppressor: a scientific tale that connects aberrant cellular ROS, the Warburg effect, and carcinogenesis. Cancer Res 72, 2468–2472.
Hernando-Herraez, I., Evano, B., Stubbs, T., Commere, P.H., Jan Bonder, M., Clark, S., Andrews, S., Tajbakhsh, S., and Reik, W. (2019). Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells. Nat Commun 10, 4361.
Hsu, Y.C., Wu, Y.T., Yu, T.H., and Wei, Y.H. (2016). Mitochondria in mesenchymal stem cell biology and cell therapy: from cellular differentiation to mitochondrial transfer. Semin Cell Dev Biol 52, 119–131.
Hu, J., Cao, Y., Xie, Y., Wang, H., Fan, Z., Wang, J., Zhang, C., Wang, J., Wu, C.T., and Wang, S. (2016). Periodontal regeneration in swine after cell injection and cell sheet transplantation of human dental pulp stem cells following good manufacturing practice. Stem Cell Res Ther 7, 130.
Infante, A., and Rodríguez, C.I. (2018). Secretome analysis of in vitro aged human mesenchymal stem cells reveals IGFBP7 as a putative factor for promoting osteogenesis. Sci Rep 8, 4632.
Kamangar, B.B., Gabillard, J.C., and Bobe, J. (2006). Insulin-like growth factor-binding protein (IGFBP)-1, -2, -3, -4, -5, and -6 and IGFBP-related protein 1 during rainbow trout postvitellogenesis and oocyte maturation: molecular characterization, expression profiles, and hormonal regulation. Endocrinology 147, 2399–2410.
Kanfi, Y., Naiman, S., Amir, G., Peshti, V., Zinman, G., Nahum, L., Bar-Joseph, Z., and Cohen, H.Y. (2012). The sirtuin SIRT6 regulates lifespan in male mice. Nature 483, 218–221.
Kenworthy, C.A., Sengupta, A., Luz, S.M., Ver Hoeve, E.S., Meda, K., Bhatnagar, S., and Abel, T. (2014). Social defeat induces changes in histone acetylation and expression of histone modifying enzymes in the ventral hippocampus, prefrontal cortex, and dorsal raphe nucleus. Neuroscience 264, 88–98.
Kim, K.S., Kim, M.S., Seu, Y.B., Chung, H.Y., Kim, J.H., and Kim, J.R. (2007a). Regulation of replicative senescence by insulin-like growth factor-binding protein 3 in human umbilical vein endothelial cells. Aging Cell 6, 535–545.
Kim, K.S., Seu, Y.B., Baek, S.H., Kim, M.J., Kim, K.J., Kim, J.H., and Kim, J.R. (2007b). Induction of cellular senescence by insulin-like growth factor binding protein-5 through a p53-dependent mechanism. Mol Biol Cell 18, 4543–4552.
Langley, E., Pearson, M., Faretta, M., Bauer, U.M., Frye, R.A., Minucci, S., Pelicci, P.G., and Kouzarides, T. (2002). Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J 21, 2383–2396.
Li, K., Fan, L., Lin, J., Heng, B.C., Deng, Z., Zheng, Q., Zhang, J., Jiang, Y., and Ge, Z. (2021). Nanosecond pulsed electric fields prime mesenchymal stem cells to peptide ghrelin and enhance chondrogenesis and osteochondral defect repair in vivo. Sci China Life Sci doi: https://doi.org/10.1007/s11427-021-1983-y.
Li, L., Mühlfeld, C., Niemann, B., Pan, R., Li, R., Hilfiker-Kleiner, D., Chen, Y., and Rohrbach, S. (2011). Mitochondrial biogenesis and PGC-1α deacetylation by chronic treadmill exercise: differential response in cardiac and skeletal muscle. Basic Res Cardiol 106, 1221–1234.
Lopez-Bermejo, A., Khosravi, J., Fernandez-Real, J.M., Hwa, V., Pratt, K. L., Casamitjana, R., Garcia-Gil, M.M., Rosenfeld, R.G., and Ricart, W. (2006). Insulin resistance is associated with increased serum concentration of IGF-binding protein-related protein 1 (IGFBP-rP1/MAC25). Diabetes 55, 2333–2339.
López-Otín, C., Blasco, M.A., Partridge, L., Serrano, M., and Kroemer, G. (2013). The hallmarks of aging. Cell 153, 1194–1217.
Ma, L., Hu, J., Cao, Y., Xie, Y., Wang, H., Fan, Z., Zhang, C., Wang, J., Wu, C.T., and Wang, S. (2019). Maintained properties of aged dental pulp stem cells for superior periodontal tissue regeneration. Aging Dis 10, 793–806.
Macrin, D., Alghadeer, A., Zhao, Y.T., Miklas, J.W., Hussein, A.M., Detraux, D., Robitaille, A.M., Madan, A., Moon, R.T., Wang, Y., et al. (2019). Metabolism as an early predictor of DPSCs aging. Sci Rep 9, 2195.
Mathew, R., Pal Bhadra, M., and Bhadra, U. (2017). Insulin/insulin-like growth factor-1 signalling (IIS) based regulation of lifespan across species. Biogerontology 18, 35–53.
Nozu, A., Hamano, S., Tomokiyo, A., Hasegawa, D., Sugii, H., Yoshida, S., Mitarai, H., Taniguchi, S., Wada, N., and Maeda, H. (2018). Senescence and odontoblastic differentiation of dental pulp cells. J Cell Physiol 234, 849–859.
Oh, J., Lee, Y.D., and Wagers, A.J. (2014). Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat Med 20, 870–880.
Ren, R., Ocampo, A., Liu, G.H., and Izpisua Belmonte, J.C. (2017). Regulation of stem cell aging by metabolism and epigenetics. Cell Metab 26, 460–474.
Rodier, F., and Campisi, J. (2011). Four faces of cellular senescence. J Cell Biol 192, 547–556.
Ryu, S.H., Kang, K., Yoo, T., Joe, C.O., and Chung, J.H. (2011). Transcriptional repression of repeat-derived transcripts correlates with histone hypoacetylation at repetitive DNA elements in aged mice brain. Exp Gerontol 46, 811–818.
Sanada, F., Taniyama, Y., Muratsu, J., Otsu, R., Shimizu, H., Rakugi, H., and Morishita, R. (2018). IGF binding protein-5 induces cell senescence. Front Endocrinol 9, 53.
Schumacher, B., Pothof, J., Vijg, J., and Hoeijmakers, J.H.J. (2021). The central role of DNA damage in the ageing process. Nature 592, 695–703.
Severino, V., Alessio, N., Farina, A., Sandomenico, A., Cipollaro, M., Peluso, G., Galderisi, U., and Chambery, A. (2013). Insulin-like growth factor binding proteins 4 and 7 released by senescent cells promote premature senescence in mesenchymal stem cells. Cell Death Dis 4, e911.
Sitar, T., Popowicz, G.M., Siwanowicz, I., Huber, R., and Holak, T.A. (2006). Structural basis for the inhibition of insulin-like growth factors by insulin-like growth factor-binding proteins. Proc Natl Acad Sci USA 103, 13028–13033.
Sun, Y., Wang, X., Fu, G., and Geng, X. (2021). MicroRNA-199a-5p accelerates nucleus pulposus cell apoptosis and IVDD by inhibiting SIRT1-mediated deacetylation of p21. Mol Ther Nucleic Acids 24, 634–645.
Tanabe, K., Liu, J., Kato, D., Kurumizaka, H., Yamatsugu, K., Kanai, M., and Kawashima, S.A. (2018). LC-MS/MS-based quantitative study of the acyl group- and site-selectivity of human sirtuins to acylated nucleosomes. Sci Rep 8, 2656.
Trounson, A., and McDonald, C. (2015). Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell 17, 11–22.
Vaziri, H., Dessain, S.K., Eaton, E.N., Imai, S.I., Frye, R.A., Pandita, T.K., Guarente, L., and Weinberg, R.A. (2001). hSIR2SIRT1 functions as an NAD-dependent p53 deacetylase. Cell 107, 149–159.
Wajapeyee, N., Serra, R.W., Zhu, X., Mahalingam, M., and Green, M.R. (2008). Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132, 363–374.
Wang, Q., He, X., Wang, B., Pan, J., Shi, C., Li, J., Wang, L., Zhao, Y., Dai, J., and Wang, D. (2021). Injectable collagen scaffold promotes swine myocardial infarction recovery by long-term local retention of transplanted human umbilical cord mesenchymal stem cells. Sci China Life Sci 64, 269–281.
Wang, Y., Liu, Y., Chen, E., and Pan, Z. (2020). The role of mitochondrial dysfunction in mesenchymal stem cell senescence. Cell Tissue Res 382, 457–462.
Wei, F., Qu, C., Song, T., Ding, G., Fan, Z., Liu, D., Liu, Y., Zhang, C., Shi, S., and Wang, S. (2012). Vitamin C treatment promotes mesenchymal stem cell sheet formation and tissue regeneration by elevating telomerase activity. J Cell Physiol 227, 3216–3224.
Wei, F., Song, T., Ding, G., Xu, J., Liu, Y., Liu, D., Fan, Z., Zhang, C., Shi, S., and Wang, S. (2013). Functional tooth restoration by allogeneic mesenchymal stem cell-based bio-root regeneration in swine. Stem Cells Dev 22, 1752–1762.
Wu, J., Wang, C., Miao, X., Wu, Y., Yuan, J., Ding, M., Li, J., and Shi, Z. (2017). Age-related insulin-like growth factor binding protein-4 overexpression inhibits osteogenic differentiation of rat mesenchymal stem cells. Cell Physiol Biochem 42, 640–650.
Xue, Y., Yan, Y., Gong, H., Fang, B., Zhou, Y., Ding, Z., Yin, P., Zhang, G., Ye, Y., Yang, C., et al. (2014). Insulin-like growth factor binding protein 4 enhances cardiomyocytes induction in murine-induced pluripotent stem cells. J Cell Biochem 115, 1495–1504.
Ye, C., Hou, W., Chen, M., Lu, J., Chen, E., Tang, L., Hang, K., Ding, Q., Li, Y., Zhang, W., et al. (2020). IGFBP7 acts as a negative regulator of RANKL-induced osteoclastogenesis and oestrogen deficiency-induced bone loss. Cell Prolif 53.
Yi, Q., Liu, O., Yan, F., Lin, X., Diao, S., Wang, L., Jin, L., Wang, S., Lu, Y., and Fan, Z. (2017). Analysis of senescence-related differentiation potentials and gene expression profiles in human dental pulp stem cells. Cells Tissues Organs 203, 1–11.
Young, K., Eudy, E., Bell, R., Loberg, M.A., Stearns, T., Sharma, D., Velten, L., Haas, S., Filippi, M.D., and Trowbridge, J.J. (2021). Decline in IGF1 in the bone marrow microenvironment initiates hematopoietic stem cell aging. Cell Stem Cell 28, 1473–1482.e7.
Zhang, W., Chen, E., Chen, M., Ye, C., Qi, Y., Ding, Q., Li, H., Xue, D., Gao, X., and Pan, Z. (2018). IGFBP7 regulates the osteogenic differentiation of bone marrow-derived mesenchymal stem cells via Wnt/β-catenin signaling pathway. FASEB J 32, 2280–2291.
Zhang, W., Qu, J., Liu, G.H., and Belmonte, J.C.I. (2020). The ageing epigenome and its rejuvenation. Nat Rev Mol Cell Biol 21, 137–150.
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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Figure S4. The expression of genes related to mitochondrial biogenesis and glycolytic key enzymes in IGFBP7 knockdown DPSCs.
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Figure S5. The expression of genes related to mitochondrial biogenesis and glycolytic key enzymes in IGFBP7 overexpressed DPSCs.
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Figure S8. The function of ROT and CoQ10 on the expression of p21, H3K36ac and SIRT1 in IGFBP7 overexpression and knockdown DPSCs.
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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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DOI: https://doi.org/10.1007/s11427-021-2096-0