DataSheet_1_Cellular and microenvironmental cues that promote macrophage fusion and foreign body response.pdf

During the foreign body response (FBR), macrophages fuse to form foreign body giant cells (FBGCs). Modulation of FBGC formation can prevent biomaterial degradation and loss of therapeutic efficacy. However, the microenvironmental cues that dictate FBGC formation are poorly understood with conflicting reports. Here, we identified molecular and cellular factors involved in driving FBGC formation in vitro. Macrophages demonstrated distinct fusion competencies dependent on monocyte differentiation. The transition from a proinflammatory to a reparative microenvironment, characterised by specific cytokine and growth factor programmes, accompanied FBGC formation. Toll-like receptor signalling licensed the formation of FBGCs containing more than 10 nuclei but was not essential for cell-cell fusion to occur. Moreover, the fibroblast-macrophage crosstalk influenced FBGC development, with the fibroblast secretome inducing macrophages to secrete more PDGF, which enhanced large FBGC formation. These findings advance our understanding as to how a specific and timely combination of cellular and microenvironmental factors is required for an effective FBR, with monocyte differentiation and fibroblasts being key players.

在异物应答（foreign body response, FBR）过程中，巨噬细胞会融合形成异物巨细胞（foreign body giant cells, FBGCs）。调控FBGC的形成可阻止生物材料降解与治疗效能损失，但目前调控FBGC形成的微环境信号尚不明晰，且相关研究报道存在矛盾。本研究在体外鉴定了驱动FBGC形成的分子与细胞因素。研究发现，巨噬细胞的融合能力存在显著差异，这取决于单核细胞的分化状态；伴随FBGC形成的是从促炎微环境向修复型微环境的转变，该转变以特定细胞因子与生长因子程序为特征。Toll样受体信号通路可促进包含10个以上细胞核的FBGC形成，但并非细胞间融合发生所必需。此外，成纤维细胞-巨噬细胞串扰会影响FBGC的发育：成纤维细胞分泌组可诱导巨噬细胞分泌更多血小板衍生生长因子（platelet-derived growth factor, PDGF），进而增强大型FBGC的形成。上述发现加深了我们对有效异物应答所需的细胞与微环境因子的特异性时序组合的理解，其中单核细胞分化与成纤维细胞发挥了关键作用。