Background Hypertrophic scarring is the most serious and unmet challenge following burn and trauma injury and often leads to pain, itching and even loss of function. However, the demand for ideal scar prevention and treatment is difficult to satisfy. We aimed to discover the effects and mechanisms of adipose-derived stem cell (ADSC) exosomes in hypertrophic scarring. Methods ADSC exosomes were isolated from the culture supernatant of ADSCs and identified by nanoparticle tracking analysis, transmission electron microscopy and western blotting. The effect of ADSC exosomes on wound healing and scar formation was detected by the wound model of BALB/c mice. We isolated myofibroblasts from hypertrophic scar tissue and detected the cell viability, proliferation and migration of myofibroblasts. In addition, collagen formation and fibrosis-related molecules were also detected. To further disclose the mechanism of ADSC exosomes on fibrosis in myofibroblasts, we detected the expression of Smad2 in hypertrophic scar tissue and normal skin and the regulatory mechanism of ADSC exosomes on Smad2. Injection of bleomycin was performed in male BALB/c mice to establish an in vivo fibrosis model while ADSC exosomes were administered to observe their protective effect. The tissue injury of mice was observed via hematoxylin and eosin and Masson staining and related testing. Results In this study, we found that ADSC exosomes could not only speed up wound healing and improve healing quality but also prevent scar formation. ADSC exosomes inhibited expression of fibrosis-related molecules such as α-smooth muscle actin, collagen I (COL1) and COL3 and inhibited the transdifferentiation of myofibroblasts. In addition, we verified that Smad2 is highly expressed in both hypertrophic scar tissue and hypertrophic fibroblasts, while ADSC exosomes downregulated the expression of Smad2 in hypertrophic fibroblasts. Further regulatory mechanism analysis revealed that microRNA-125b-5p (miR-125b-5p) is highly expressed in ADSC exosomes and binds to the 3' untranslated region of Smad2, thus inhibiting its expression. In vivo experiments also revealed that ADSC exosomes could alleviate bleomycin-induced skin fibrosis and downregulate the expression of Smad2. Conclusions We found that ADSC exosomes could alleviate hypertrophic scars via the suppression of Smad2 by the specific delivery of miR-125b-5p.

中文翻译：

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脂肪干细胞外泌体递送的 miR-125b-5p 通过抑制 Smad2 减轻肥厚性疤痕形成。


背景 肥厚性疤痕是烧伤和外伤后最严重且未解决的挑战，常常导致疼痛、瘙痒甚至功能丧失。然而，理想的疤痕预防和治疗的需求很难满足。我们的目的是发现脂肪源性干细胞（ADSC）外泌体在肥厚性疤痕中的作用和机制。方法从ADSCs培养上清液中分离出ADSC外泌体，并通过纳米颗粒追踪分析、透射电镜和蛋白质印迹法进行鉴定。通过BALB/c小鼠伤口模型检测ADSC外泌体对伤口愈合和疤痕形成的影响。我们从肥厚性疤痕组织中分离出肌成纤维细胞，并检测肌成纤维细胞的细胞活力、增殖和迁移。此外，还检测到胶原蛋白形成和纤维化相关分子。为了进一步揭示ADSC外泌体对肌成纤维细胞纤维化的作用机制，我们检测了肥厚性疤痕组织和正常皮肤中Smad2的表达情况以及ADSC外泌体对Smad2的调节机制。雄性BALB/c小鼠注射博莱霉素建立体内纤维化模型，同时给予ADSC外泌体观察其保护作用。通过苏木精、伊红、Masson染色及相关检测观察小鼠组织损伤情况。结果在本研究中，我们发现ADSC外泌体不仅可以加速伤口愈合、提高愈合质量，还可以预防疤痕形成。 ADSC外泌体抑制α-平滑肌肌动蛋白、I型胶原蛋白（COL1）和COL3等纤维化相关分子的表达，并抑制肌成纤维细胞的转分化。 此外，我们验证了Smad2在肥厚性疤痕组织和肥厚性成纤维细胞中高表达，而ADSC外泌体下调肥厚性成纤维细胞中Smad2的表达。进一步的调控机制分析显示，microRNA-125b-5p（miR-125b-5p）在ADSC外泌体中高表达，并与Smad2的3'非翻译区结合，从而抑制其表达。体内实验还表明，ADSC外泌体可以减轻博来霉素诱导的皮肤纤维化并下调Smad2的表达。结论 我们发现 ADSC 外泌体可以通过特异性递送 miR-125b-5p 来抑制 Smad2，从而减轻增生性疤痕。