From the Department of Plastic and Reconstructive Surgery, Asahi General Hospital.
Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University.
Plast Reconstr Surg. 2023 Nov 1;152(5):1011-1021. doi: 10.1097/PRS.0000000000010388. Epub 2023 Mar 8.
Transplantation of adipose-derived mesenchymal stem cells (ADSCs) has been reported to improve the severity of chronic lymphedema. Extracellular vesicles (EVs) derived from mesenchymal stem cells have been reported to exert effects such as the promotion of angiogenesis, suppression of inflammation, and regeneration of damaged organs. In this study, the authors show that lymphangiogenesis was induced by EVs derived from ADSCs and reveal the therapeutic potential of these EVs for the treatment of lymphedema.
The authors examined the in vitro effects of ADSC-EVs to lymphatic endothelial cells (LECs). Next, they conducted an in vivo analysis of ADSC-EVs to mouse lymphedema models. Bioinformatics analysis was also performed to evaluate the implications of the altered microRNA expression.
The authors showed that ADSC-EVs promoted the proliferation, migration, and tube formation of LECs, and the gene expression of lymphatic markers was elevated in the ADSC-EV-treated group. Notably, a mouse lymphedema model revealed that legs treated with ADSC-EVs had markedly improved edema, with increased numbers of capillary vessels and lymphatic channels. Bioinformatics analysis revealed that ADSC-EV-associated microRNAs, such as miR-199a-3p, miR-145-5p, miR-143-3p, miR-377-3p, miR-100-3p, miR-29a-3p, miR-495-3p, and miR-29c-3p, targeted mouse double minute 2 homolog, which contributed to the stability of hypoxia-inducible factor 1α and resulted in angiogenesis and lymphangiogenesis in LECs.
The present study showed lymphangiogenic effects of ADSC-EVs, which will lead to new treatment options for chronic lymphedema. Cell-free therapy with EVs has fewer potential risks, such as poor engraftment efficiency and potential tumor formation, than stem cell transplantation and could be a promising tool for patients with lymphedema.
This study may open up new possibilities for novel therapies for lymphedema.
脂肪间充质干细胞（ADSCs）的移植已被报道可改善慢性淋巴水肿的严重程度。间充质干细胞衍生的细胞外囊泡（EVs）已被报道具有促进血管生成、抑制炎症和损伤器官再生等作用。在这项研究中，作者表明 ADSC-EVs 诱导了淋巴管生成，并揭示了这些 EVs 治疗淋巴水肿的治疗潜力。
作者检查了 ADSC-EVs 对淋巴管内皮细胞（LECs）的体外作用。接下来，他们对 ADSC-EVs 治疗小鼠淋巴水肿模型进行了体内分析。还进行了生物信息学分析，以评估改变的 microRNA 表达的意义。
作者表明 ADSC-EVs 促进了 LECs 的增殖、迁移和管形成，并且在 ADSC-EV 处理组中淋巴管标记物的基因表达升高。值得注意的是，在小鼠淋巴水肿模型中，用 ADSC-EVs 处理的腿部明显改善了水肿，毛细血管和淋巴管的数量增加。生物信息学分析表明，ADSC-EV 相关的 microRNAs，如 miR-199a-3p、miR-145-5p、miR-143-3p、miR-377-3p、miR-100-3p、miR-29a-3p、miR-495-3p 和 miR-29c-3p，靶向小鼠双微体 2 同源物，促进了缺氧诱导因子 1α 的稳定性，并导致 LECs 中的血管生成和淋巴管生成。
本研究表明 ADSC-EVs 具有淋巴管生成作用，这将为慢性淋巴水肿的新治疗方法提供依据。与干细胞移植相比，细胞外囊泡的无细胞治疗具有较少的潜在风险，如植入效率差和潜在的肿瘤形成，并且可能成为淋巴水肿患者的有前途的治疗工具。
这项研究可能为淋巴水肿的新疗法开辟新的可能性。
