Fibromodulin reduces scar formation in adult cutaneous wounds by eliciting a fetal-like phenotype.
Fibromodulin reduces scar formation in adult cutaneous wounds by eliciting a fetal-like phenotype.
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DOI：
10.1038/sigtrans.2017.50
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发表时间：
2017
影响因子：
39.3
通讯作者：
Soo C
中科院分区：
文献类型：
--
作者：
Zheng Z;James AW;Li C;Jiang W;Wang JZ;Chang GX;Lee KS;Chen F;Berthiaume EA;Chen Y;Pan HC;Chen EC;Li W;Zhao Z;Zhang X;Ting K;Soo C
阻断转化生长因子 (TGF)β1 信号转导一直是减少疤痕的核心策略；然而，这种方法似乎收效甚微。在这里，我们发现纤维调节蛋白（FMOD）是一种对正常胶原纤维生成至关重要的 59 kD 富含亮氨酸的小蛋白聚糖，可显着减少疤痕形成，同时增加成年啮齿动物模型和猪伤口的疤痕强度，模拟人类皮肤疤痕修复。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 自诱导和纤维化细胞外基质积累，将促迁移/收缩细胞信号与促纤维化信号分离。因此，FMOD 加速 TGFβ1 反应性成体成纤维细胞迁移、肌成纤维细胞转化和功能。此外，我们的研究结果强烈表明，通过精心协调 TGFβ1 活性而不是不加区别地阻断 TGFβ1，FMOD 在体外成人真皮成纤维细胞和体内成人皮肤伤口中引发胎儿样细胞和分子表型，这是以前未描述过的生命系统的独特反应。总而言之，这项研究阐明了 FMOD 在其结构支持功能之外的信号调节活性，并强调了基于 FMOD 的疗法用于皮肤伤口修复的潜力。
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.
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