Following tendon injury, the development of fibrotic healing response impairs tendon function and restricts tendon motion. Peritendinous tissue fibrosis poses a major clinical problem in hand surgery. Communication between macrophages and tendon cells has a critical role in regulating the tendon-healing process. Yet, the mechanisms employed by macrophages to control peritendinous fibrosis are not fully understood. Here we analyze the role of macrophages in tendon adhesion in mice by pharmacologically depleting them. Such macrophage-depleted mice have less peritendinous fibrosis formation around the injured tendon compared with wild-type littermates. Macrophage-depleted mice restart fibrotic tendon healing by treatment with bone marrow macrophage-derived exosomes. We show that bone marrow macrophages secrete exosomal miR-21-5p that directly targets Smad7, leading to the activation of fibrogenesis in tendon cells. These results demonstrate that intercellular crosstalk between bone marrow macrophages and tendon cells is mediated by macrophage-derived miR-21-5p-containing exosomes that control the fibrotic healing response, providing potential targets for the prevention and treatment of tendon adhesion.

肌腱损伤后，纤维化愈合反应的发展会削弱肌腱功能并限制肌腱运动。牙周组织纤维化在手外科手术中提出了主要的临床问题。巨噬细胞与肌腱细胞之间的通讯在调节肌腱愈合过程中起着至关重要的作用。但是，尚未完全了解巨噬细胞控制周缘纤维化的机制。在这里，我们通过药理学上的研究来分析巨噬细胞在小鼠肌腱粘连中的作用。与野生型同窝仔相比，这种巨噬细胞耗竭型小鼠在受损肌腱周围的蠕动性纤维化形成较少。巨噬细胞耗竭的小鼠通过用骨髓巨噬细胞衍生的外来体治疗重新开始纤维化肌腱愈合。我们显示，骨髓巨噬细胞分泌直接靶向Smad7的外泌体miR-21-5p，从而导致肌腱细胞中纤维化的激活。这些结果表明，骨髓巨噬细胞和肌腱细胞之间的细胞间串扰是由巨噬细胞衍生的含miR-21-5p的囊泡介导的，该囊泡控制纤维化愈合反应，为预防和治疗肌腱粘连提供了潜在的靶标。