Qiao Wei, Xie Huizhi, Fang Jinghan, Shen Jie, Li Wenting, Shen Danni, Wu Jun, Wu Shuilin, Liu Xuanyong, Zheng Yufeng, Cheung Kenneth M C, Yeung Kelvin W K
Department of Orthopaedics & Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, 999077, China; Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China.
State Key Laboratory for Turbulence and Complex System and Department of Materials Science and Engineering, College of Engineering, Peking University, Beijing, 100871, PR China.
Biomaterials. 2021 Sep;276:121038. doi: 10.1016/j.biomaterials.2021.121038. Epub 2021 Jul 28.
Macrophage has been gradually recognized as a central regulator in tissue regeneration, and the study of how macrophage mediates biomaterials-induced bone regeneration through immunomodulatory pathway becomes popular. However, the current understanding on the roles of different macrophage phenotypes in regulating bone tissue regeneration remains controversial. In this study, we demonstrate that sequential infiltration of heterogeneous phenotypes of macrophages triggered by bio-metal ions effectively facilitates bone healing in bone defect. Indeed, M1 macrophages promote the recruitment and early commitment of osteogenic and angiogenic progenitors, while M2 macrophages and osteoclasts support the deposition and mineralization of the bone matrix, as well as the maturation of blood vessels. Moreover, we have identified a group of bone biomaterial-related multinucleated cells that behave similarly to M2 macrophages with wound-healing features rather than participate in the bone resorption cascade similarly to osteoclasts. Our study shows how sequential activation of macrophage-osteoclast lineage contribute to a highly orchestrated immune response in the bone tissue microenvironment around biomaterials to regulate the complex biological process of bone healing. Therefore, we believe that the temporal activation pattern of heterogeneous macrophage phenotypes should be considered when the next generation of biomaterials for bone regeneration is engineered.
巨噬细胞已逐渐被公认为组织再生的核心调节因子，关于巨噬细胞如何通过免疫调节途径介导生物材料诱导的骨再生的研究也日益受到关注。然而，目前对于不同巨噬细胞表型在调节骨组织再生中的作用的理解仍存在争议。在本研究中，我们证明了生物金属离子触发的巨噬细胞异质性表型的顺序性浸润有效地促进了骨缺损处的骨愈合。事实上，M1巨噬细胞促进成骨和血管生成祖细胞的募集和早期定向分化，而M2巨噬细胞和破骨细胞则支持骨基质的沉积和矿化以及血管的成熟。此外，我们鉴定出了一组与骨生物材料相关的多核细胞，它们的行为类似于具有伤口愈合特征的M2巨噬细胞，而不是像破骨细胞那样参与骨吸收级联反应。我们的研究展示了巨噬细胞-破骨细胞谱系的顺序性激活如何在生物材料周围的骨组织微环境中促成高度协调的免疫反应，从而调节骨愈合这一复杂的生物学过程。因此，我们认为在设计下一代用于骨再生的生物材料时，应考虑异质性巨噬细胞表型的时间激活模式。
