Wang Liang, Wang Xu, Wu Jicenyuan, Chen Junyu, He Zihan, Wang Jian, Zhang Xin
State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
Department of Prosthodontics and Implantology, The Affiliated Stomatological Hospital of Guizhou Medical University, Guiyang, Guizhou, 550004, China.
Adv Healthc Mater. 2025 Jul;14(19):e2500274. doi: 10.1002/adhm.202500274. Epub 2025 May 9.
Vascularization has been considered an essential strategy for bone regeneration and can be promoted by magnesium ions (Mg). During angiogenesis, the differentiation of endothelial cells (ECs) into tip cell is a critical step since it controls the growth direction and pattern of new vascular sprouts. While several studies have noted the pro-angiogenic effects of Mg, however, their specific influence on tip cell formation is unclear. Therefore, this research seeks to examine the impact of Mg on tip cells and elucidate the potential mechanisms involved. The results reveal that Mg shows good compatibility and stimulates ECs to migrate and invade in vitro. Moreover, Mg enhances EC spheroids sprouting and elevates the expression of genes linked to tip cells. The underlying mechanisms are that Mg facilitates tip cell differentiation via the VEGFA-VEGFR2/Notch1 signaling pathway crosstalk and promotes migration and filopodia formation of tip cells and proliferation of stalk cells by inducing YAP nuclear translocation, culminating in the maturation of vascular networks. Furthermore, EC spheroids stimulated by Mg load in hydrogel enhance vascularized bone regeneration in vivo. These findings enrich the understanding of how Mg influence blood vessel formation and provide practical strategies for the development and design of magnesium-based biomaterials.
血管化被认为是骨再生的一项重要策略，镁离子（Mg）可促进血管化。在血管生成过程中，内皮细胞（ECs）分化为顶端细胞是关键步骤，因为它控制着新血管芽的生长方向和模式。虽然多项研究已指出镁的促血管生成作用，但其对顶端细胞形成的具体影响尚不清楚。因此，本研究旨在探讨镁对顶端细胞的影响，并阐明其中潜在的机制。结果显示，镁具有良好的生物相容性，并能在体外刺激内皮细胞迁移和侵袭。此外，镁可增强内皮细胞球体的出芽，并提高与顶端细胞相关基因的表达。潜在机制是，镁通过VEGFA-VEGFR2/Notch1信号通路串扰促进顶端细胞分化，并通过诱导YAP核转位促进顶端细胞的迁移和丝状伪足形成以及茎细胞的增殖，最终导致血管网络成熟。此外，水凝胶中负载镁刺激的内皮细胞球体可增强体内血管化骨再生。这些发现丰富了对镁如何影响血管形成的理解，并为镁基生物材料的开发和设计提供了实用策略。
