Jiang Wenlu, Pang Xiaoxiao, Ha Pin, Li Chenshuang, Chang Grace Xinlian, Zhang Yuxin, Bossong Lawrence A, Ting Kang, Soo Chia, Zheng Zhong
Division of Plastic and Reconstructive Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral, Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing, 401147, China.
Nat Commun. 2025 Apr 12;16(1):3499. doi: 10.1038/s41467-025-58906-z.
Activated myofibroblasts deposit extracellular matrix material to facilitate rapid wound closure that can heal scarlessly during fetal development. However, adult myofibroblasts exhibit a relatively long life and persistent function, resulting in scarring. Thus, understanding how fetal and adult tissue regeneration differs may serve to identify factors that promote more optimal wound healing in adults with little or less scarring. We previously found that matricellular proteoglycan fibromodulin is one such factor promoting more optimal repair, but the underlying molecular and cellular mechanisms for these effects have not been fully elucidated. Here, we find that fibromodulin induces myofibroblast apoptosis after wound closure to reduce scarring in small and large animal models. Mechanistically, fibromodulin accelerates and prolongs the formation of the interleukin 1β-interleukin 1 receptor type 1-interleukin 1 receptor accessory protein ternary complex to increase the apoptosis of myofibroblasts and keloid- and hypertrophic scar-derived cells. As the persistence of myofibroblasts during tissue regeneration is a key cause of fibrosis in most organs, fibromodulin represents a promising, broad-spectrum anti-fibrotic therapeutic.
活化的肌成纤维细胞会沉积细胞外基质材料，以促进伤口快速愈合，在胎儿发育过程中这种愈合可以不留疤痕。然而，成年肌成纤维细胞具有相对较长的寿命和持续的功能，会导致疤痕形成。因此，了解胎儿和成人组织再生的差异，可能有助于识别促进成人伤口更理想愈合且疤痕较少或无疤痕的因素。我们之前发现，基质细胞蛋白聚糖纤维调节素就是这样一种促进更理想修复的因素，但这些作用的潜在分子和细胞机制尚未完全阐明。在这里，我们发现纤维调节素在伤口闭合后诱导肌成纤维细胞凋亡，以减少大小动物模型中的疤痕形成。从机制上讲，纤维调节素加速并延长白细胞介素1β-白细胞介素1受体1型-白细胞介素1受体辅助蛋白三元复合物的形成，以增加肌成纤维细胞以及瘢痕疙瘩和增生性瘢痕来源细胞的凋亡。由于组织再生过程中肌成纤维细胞的持续存在是大多数器官纤维化的关键原因，纤维调节素是一种有前景的广谱抗纤维化治疗药物。
