PDF(Pubmed)
Abstract：
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.
摘要：
在异物响应（FBR）期间，巨噬细胞融合形成异物巨细胞(FBGCs)。FBGC形成的调节可以防止生物材料降解和治疗功效的损失。然而,在相互矛盾的报道中，对决定FBGC形成的微环境线索知之甚少。这里,我们确定了在体外驱动FBGC形成的分子和细胞因子。巨噬细胞表现出不同的融合能力，取决于单核细胞分化。从促炎到修复微环境的转变，以特定的细胞因子和生长因子程序为特征，伴随FBGC形成。Toll样受体信号传导许可了含有10个以上细胞核的FBGC的形成,但对于细胞-细胞融合的发生不是必需的。此外，成纤维细胞-巨噬细胞串扰影响FBGC的发育，随着成纤维细胞分泌组诱导巨噬细胞分泌更多的PDGF，这增强了大FBGC的形成。这些发现促进了我们对细胞和微环境因素的特定和及时组合是如何需要有效的FBR的理解。单核细胞分化和成纤维细胞是关键角色。
