Extracellular Vesicles from Adipose-Derived Stem Cells Relieve Extremity Lymphedema in Mouse Models

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICAL RELEVANCE STATEMENT: This study may open up new possibilities for novel therapies for lymphedema.