Exosomes from human adipose-derived mesenchymal stem cells inhibit production of extracellular matrix in keloid fibroblasts via downregulating transforming growth factor-β2 and Notch-1 expression

Keloids are an excessive tissue response to dermal damage, characterized by uncontrolled growth and a high recurrence rate after various treatments. Abnormalities with the extracellular matrix (ECM) are one of the most important contributing factors to the formation of keloids. Although exosomes from human adipose-derived mesenchymal stem cells (adMSC-Exos) have been shown to promote repair and regeneration in wounds, they have seldom been studied for the treatment of keloids. In this study, we aimed to investigate the effects of adMSC-Exos on ECM remodeling in keloids using both <i>in vitro</i> and <i>ex vivo</i> models. The results showed that adMSC-Exos inhibited gene and protein expression of collagen I (<i>COL-1</i>), collagen III (<i>COL-3</i>), fibronectin (<i>FN</i>), and α-smooth muscle actin (<i>α-SMA</i>) in keloid fibroblasts (KFs). Furthermore, using an <i>ex vivo</i> tissue explant model, we found that adMSC-Exos significantly suppressed COL production and disrupted the microvessel stucture. We also demonstrated that adMSC-Exos inhibited the protein expression of Smad3 and Notch-1, and the expression of transforming growth factor β2 (<i>TGF-β2</i>) in KFs, and promoted the expression of <i>TGF-β3</i>. These findings largely explain the mechanisms underlying the inhibition of ECM production in keloids by adMSC-Exos. In conclusion, our results revealed that adMSC-Exos effectively inhibited the production of ECM in keloids, which provides a new potential alternative for the systemic treatment of keloids.

瘢痕疙瘩（Keloids）是皮肤损伤引发的过度组织反应，其特征为生长失控且经多种治疗后复发率居高不下。细胞外基质（extracellular matrix, ECM）异常是瘢痕疙瘩形成的关键致病因素之一。尽管人脂肪来源间充质干细胞外泌体（adMSC-Exos）已被证实可促进伤口修复与再生，但目前鲜有研究将其应用于瘢痕疙瘩的治疗。本研究旨在通过体外（in vitro）与离体（ex vivo）模型，探究adMSC-Exos对瘢痕疙瘩组织中细胞外基质重塑的影响。实验结果显示，adMSC-Exos可显著抑制瘢痕疙瘩成纤维细胞（keloid fibroblasts, KFs）中Ⅰ型胶原（COL-1）、Ⅲ型胶原（COL-3）、纤连蛋白（FN）以及α-平滑肌肌动蛋白（α-SMA）的基因与蛋白表达。进一步借助离体组织外植模型，本研究发现adMSC-Exos可有效抑制胶原生成并破坏微血管结构。此外，本研究证实adMSC-Exos可下调瘢痕疙瘩成纤维细胞中Smad3、Notch-1的蛋白表达，以及转化生长因子β2（TGF-β2）的表达，同时上调转化生长因子β3（TGF-β3）的表达。上述发现系统阐明了adMSC-Exos抑制瘢痕疙瘩细胞外基质生成的潜在作用机制。综上，本研究结果表明adMSC-Exos可有效抑制瘢痕疙瘩的细胞外基质过度生成，为瘢痕疙瘩的系统性治疗提供了全新的潜在替代方案。