miR-125b-5p delivered by adipose-derived stem cell exosomes alleviates hypertrophic scarring by suppressing Smad2.

IF 6.3 1区医学 Q1 DERMATOLOGY Burns & Trauma Pub Date : 2024-05-18 eCollection Date: 2024-01-01 DOI:10.1093/burnst/tkad064

Chaolei Xu, Hao Zhang, Chen Yang, Ying Wang, Kejia Wang, Rui Wang, Wei Zhang, Chao Li, Chenyang Tian, Chao Han, Mengyang Li, Xu Liu, Yunwei Wang, Yan Li, Jian Zhang, Yu Li, Liang Luo, Yage Shang, Lixia Zhang, Yuxi Chen, Kuo Shen, Dahai Hu

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Abstract

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.

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脂肪来源干细胞外泌体递送的 miR-125b-5p 通过抑制 Smad2 减轻肥厚性瘢痕。

背景：肥厚性瘢痕是烧伤和创伤后最严重、最难以解决的难题，通常会导致疼痛、瘙痒，甚至丧失功能。然而，理想的疤痕预防和治疗很难满足人们的需求。我们的目的是发现脂肪源性干细胞（ADSC）外泌体在增生性瘢痕中的作用和机制：方法：从 ADSCs 的培养上清液中分离出 ADSC 外泌体，并通过纳米颗粒追踪分析、透射电子显微镜和 Western 印迹法对其进行鉴定。通过 BALB/c 小鼠伤口模型检测 ADSC 外泌体对伤口愈合和瘢痕形成的影响。我们从增生性瘢痕组织中分离出了肌成纤维细胞，并检测了肌成纤维细胞的活力、增殖和迁移。此外，还检测到胶原蛋白的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，我们检测了肥厚性瘢痕组织和正常皮肤中 Smad2 的表达以及 ADSC 外泌体对 Smad2 的调控机制。在雄性BALB/c小鼠体内注射博莱霉素建立体内纤维化模型，同时注射ADSC外泌体观察其保护作用。通过苏木精、伊红和马森染色及相关测试观察小鼠的组织损伤：结果：本研究发现，ADSC外泌体不仅能加速伤口愈合，提高愈合质量，还能防止疤痕形成。ADSC 外泌体抑制了纤维化相关分子（如α-平滑肌肌动蛋白、胶原 I（COL1）和 COL3）的表达，并抑制了肌成纤维细胞的转分化。此外，我们还验证了Smad2在增生性瘢痕组织和增生性成纤维细胞中均有高表达，而ADSC外泌体能下调Smad2在增生性成纤维细胞中的表达。进一步的调控机制分析发现，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。体内实验还发现，ADSC外泌体可以缓解博莱霉素诱导的皮肤纤维化，并下调Smad2的表达：我们发现 ADSC 外泌体可以通过特异性递送 miR-125b-5p 抑制 Smad2 来缓解增生性疤痕。

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来源期刊

Burns & Trauma 医学-皮肤病学

CiteScore

8.40

自引率

9.40%

发文量

186

审稿时长

6 weeks

期刊介绍： The first open access journal in the field of burns and trauma injury in the Asia-Pacific region, Burns & Trauma publishes the latest developments in basic, clinical and translational research in the field. With a special focus on prevention, clinical treatment and basic research, the journal welcomes submissions in various aspects of biomaterials, tissue engineering, stem cells, critical care, immunobiology, skin transplantation, and the prevention and regeneration of burns and trauma injuries. With an expert Editorial Board and a team of dedicated scientific editors, the journal enjoys a large readership and is supported by Southwest Hospital, which covers authors'' article processing charges.