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Magnesium Ions Promote In Vitro Rat Bone Marrow Stromal Cell Angiogenesis Through Notch Signaling

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Abstract

Bone defects are often caused by trauma or surgery and can lead to delayed healing or even bone nonunion, thereby resulting in impaired function of the damaged site. Magnesium ions and related metallic materials play a crucial role in repairing bone defects, but the mechanism remains unclear. In this study, we induced the angiogenic differentiation of bone marrow stromal cells (BMSCs) with different concentrations of magnesium ions. The mechanism was investigated using γ-secretase inhibitor (DAPT) at different time points (7 and 14 days). Angiogenesis, differentiation, migration, and chemotaxis were detected using the tube formation assay, wound-healing assay, and Transwell assay. Besides, we analyzed mRNA expression and the angiogenesis-related protein levels of genes by RT-qPCR and western blot. We discovered that compared with other concentrations, the 5 mM magnesium ion concentration was more conducive to forming tubes. Additionally, hypoxia-inducible factor 1 alpha (Hif-1α) and endothelial nitric oxide (eNOS) expression both increased (p < 0.05). After 7 and 14 days of induction, 5 mM magnesium ion group tube formation, migration, and chemotaxis were enhanced, and the expression of Notch pathway genes increased. Moreover, expression of the Notch target genes hairy and enhancer of split 1 (Hes1) and Hes5 (hairy and enhancer of split 5), as well as the angiogenesis-related genes Hif-1α and eNOS, were enhanced (p < 0.05). However, these trends did not occur when DAPT was applied. This indicates that 5 mM magnesium ion is the optimal concentration for promoting the angiogenesis and differentiation of BMSCs in vitro. By activating the Notch signaling pathway, magnesium ions up-regulate the downstream genes Hes1 and Hes5 and the angiogenesis-related genes Hif-1α and eNOS, thereby promoting the angiogenesis differentiation of BMSCs. Additionally, magnesium ion-induced differentiation enhances the migration and chemotaxis of BMSCs. Thus, we can conclude that magnesium ions and related metallic materials promote angiogenesis to repair bone defects. This provides the rationale for developing artificial magnesium-containing bone materials through tissue engineering.

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Funding

This research was continuously funded by National Natural Science Foundation of China (No. 82172432; 82102568 and 82001319), National & Local Joint Engineering Research Center of Orthopaedic Biomaterials (XMHT20190204007), Shenzhen High-level Hospital Construction Fund, Shenzhen Key Medical Discipline Construction Fund (No. SZXK023), Shenzhen “San-Ming” Project of Medicine (No. SZSM201612092), Research and Development Projects of Shenzhen (No. Z2021N054), Guangdong Basic and Applied Basic Research Foundation (No. 2021A1515012586), Bethune Charitable Foundation and CSPC Osteoporosis Research Foundation Project (No. G-X-2020–1107-21), and The Scientific Research Foundation of PEKING UNIVERSITY SHENZHEN HOSPITAL (No. KYQD2021099).

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Author notes

  1. Haotian Qin, Jian Weng and Bo Zhou contributed equally to this work.

Authors and Affiliations

  1. Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China

    Haotian Qin, Jian Weng, Weifei Zhang, Guoqing Li, Yingqi Chen, Tiantian Qi, Yuanchao Zhu, Fei Yu & Hui Zeng

  2. National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, 518036, China

    Haotian Qin, Jian Weng, Weifei Zhang, Guoqing Li, Yingqi Chen, Tiantian Qi, Yuanchao Zhu, Fei Yu & Hui Zeng

  3. Department of Hand & Microsurgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China

    Bo Zhou

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  5. Guoqing Li
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  9. Fei Yu
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  10. Hui Zeng
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Contributions

Conceptualization, H.Z. and F.Y.; methodology, T.Q. and Y.Z.; software, W.Z. and G.L.; formal analysis, J.W. and B.Z.; investigation, H.Q., J.W., and B.Z.; data curation, Y.Z., Y.C., and W.Z.; writing—original draft preparation, H.Q., J.W., and B.Z.; writing—review and editing, F.Y. and H.Z.; supervision, F.Y. and H.Z.; funding acquisition, F.Y. and H.Z. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Fei Yu or Hui Zeng.

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Qin, H., Weng, J., Zhou, B. et al. Magnesium Ions Promote In Vitro Rat Bone Marrow Stromal Cell Angiogenesis Through Notch Signaling. Biol Trace Elem Res 201, 2823–2842 (2023). https://doi.org/10.1007/s12011-022-03364-7

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