Blocking transforming growth factor (TGF)β1 signal transduction has been a central strategy for scar reduction; however, this approach appears to be minimally effective. Here, we show that fibromodulin (FMOD), a 59-kD small leucine-rich proteoglycan critical for normal collagen fibrillogenesis, significantly reduces scar formation while simultaneously increasing scar strength in both adult rodent models and porcine wounds, which simulate human cutaneous scar repair. Mechanistically, FMOD uncouples pro-migration/contraction cellular signals from pro-fibrotic signaling by selectively enhancing SMAD3-mediated signal transduction, while reducing AP-1-mediated TGFβ1 auto-induction and fibrotic extracellular matrix accumulation. Consequently, FMOD accelerates TGFβ1-responsive adult fibroblast migration, myofibroblast conversion, and function. Furthermore, our findings strongly indicate that, by delicately orchestrating TGFβ1 activities rather than indiscriminately blocking TGFβ1, FMOD elicits fetal-like cellular and molecular phenotypes in adult dermal fibroblasts in vitro and adult cutaneous wounds in vivo, which is a unique response of living system undescribed previously. Taken together, this study illuminates the signal modulating activities of FMOD beyond its structural support functions, and highlights the potential for FMOD-based therapies to be used in cutaneous wound repair.

中文翻译：

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纤维调节蛋白通过引发胎儿样表型减少成人皮肤伤口中的疤痕形成。

阻断转化生长因子（TGF）β1信号转导已成为减少疤痕的主要策略。但是，这种方法似乎效果最低。在这里，我们显示出纤维调节蛋白（FMOD），一种对正常胶原原纤维形成至关重要的59 kD富含亮氨酸的小蛋白多糖，可显着减少疤痕的形成，同时增加成年啮齿动物模型和猪伤口（模拟人类皮肤瘢痕修复）的瘢痕强度。从机制上讲，FMOD通过选择性增强SMAD3介导的信号转导，同时减少AP-1介导的TGFβ1自动诱导和纤维化细胞外基质的积累，将促迁移/收缩细胞信号与促纤维化信号解耦。因此，FMOD加速了对TGFβ1反应的成年成纤维细胞的迁移，成肌纤维细胞的转化和功能。体外和成人体内皮肤伤口，这是先前未描述的生命系统的独特反应。两者合计，这项研究阐明了FMOD超出其结构支持功能的信号调节活性，并强调了基于FMOD的疗法在皮肤伤口修复中的潜力。