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Functional Regulatory Mechanisms Underlying Bone Marrow Mesenchymal Stem Cell Senescence During Cell Passages

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Abstract

Mesenchymal stem cell (MSC) transplantation is an effective periodontal regenerative therapy. MSCs are multipotent, have self-renewal ability, and can differentiate into periodontal cells. However, senescence is inevitable for MSCs. In vitro, cell senescence can be induced by long-term culture with/without cell passage. However, the regulatory mechanism of MSC senescence remains unclear. Undifferentiated MSC-specific transcription factors can regulate MSC function. Herein, we identified the regulatory transcription factors involved in MSC senescence and elucidated their mechanisms of action. We cultured human MSCs (hMSCs) with repetitive cell passages to induce cell senescence and evaluated the mRNA and protein expression of cell senescence-related genes. Additionally, we silenced the cell senescence-induced transcription factors, GATA binding protein 6 (GATA6) and SRY-box 11 (SOX11), and investigated senescence-related signaling pathways. With repeated passages, the number of senescent cells increased, while the cell proliferation capacity decreased; GATA6 mRNA expression was upregulated and that of SOX11 was downregulated. Repetitive cell passages decreased Wnt and bone morphogenetic protein (BMP) signaling pathway-related gene expression. Silencing of GATA6 and SOX11 regulated Wnt and BMP signaling pathway-related genes and affected cell senescence-related genes; moreover, SOX11 silencing regulated GATA6 expression. Hence, we identified them as pair of regulatory transcription factors for cell senescence in hMSCs via the Wnt and BMP signaling pathways.

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Acknowledgements

We thank Dr. Hideki Shiba for helpful discussion. A portion of this work was carried out with the material support of the Research Facility of Hiroshima University Faculty of Dentistry.

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  1. These authors contributed equally: T. Iwata, S. Ishida

Authors and Affiliations

  1. Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8553, Japan

    T. Iwata, N. Mizuno, S. Ishida, M. Kajiya, T. Nagahara, E. Kaneda-Ikeda, M. Yoshioka, S. Munenaga, K. Ouhara, T. Fujita, H. Kawaguchi & H. Kurihara

  2. Department of General Dentistry, Hiroshima University Hospital, Hiroshima, 734-8553, Japan

    S. Munenaga & H. Kawaguchi

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  1. T. Iwata
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by T.I., N.M., S.I., M.K., T.N., E.K.-I., M.Y., S.M., and K.O. H.K. supervised all aspects of the study as the senior investigator and director of the laboratory. The first draft of the paper was written by T.I. and all authors commented on previous versions of the paper. All authors read and approved the final paper.

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Correspondence to T. Iwata.

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This study was approved by the Ethics Committee of Hiroshima University Faculty of Dentistry (Hiroshima, Japan; Approval Numbers: E-19 and E-422-2) and performed in accordance with the Declaration of Helsinki (2008) of the World Medical Association.

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Iwata, T., Mizuno, N., Ishida, S. et al. Functional Regulatory Mechanisms Underlying Bone Marrow Mesenchymal Stem Cell Senescence During Cell Passages. Cell Biochem Biophys 79, 321–336 (2021). https://doi.org/10.1007/s12013-021-00969-y

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