Exosomes Derived from Hypoxia-conditioned Adipose-derived Mesenchymal Stem Cells Enhance Lymphangiogenesis via Modulation of miR-129/HMGB1/AKT Pathway

Abstract

Background Exosomes from adipose-derived mesenchymal stem cells (ADSCs) play an important role in lymphangiogenesis; however, the underlying mechanisms are not fully understood. In this study, we aimed to investigate the function of exosomes secreted by hypoxia-conditioned ADSCs in lymphangiogenesis and explore the potential molecular mechanisms.Methods Exosomes were extracted from ADSCs cultured under hypoxia or normoxia conditions. The uptake of exosomes by LECs was detected by immunofluorescence staining. The effects of exosomes on the viability, migration, and tube formation of LECs were determined by CCK-8 assay, migration assay, and tube formation assay, respectively. Molecules and pathway involved in lymphangiogenesis mediated by ADSC-derived exosomes were analyzed by luciferase reporter assay, qRT-PCR, and Western blot.Results Hypoxia ADSC-derived exosomes (H-ADSC/exos) significantly enhanced the proliferation, migration, and tube formation of LECs. Hypoxia decreased the expression of miR-129 in ADSC-derived exosomes. Overexpression of miR-129 counteracted the promoting effect of H-ADSC/exos on lymphangiogenesis. In addition, decreased exosomal miR-129 expression resulted in upregulation of HMGB1 in LECs, which led to AKT activation and lymphangiogenesis enhancement. Our data reveal that exosomes derived from hypoxia-conditioned ADSCs induce lymphangiogenesis, and this effect is mediated by miR-129/HMGB1/AKT signaling. Conclusions Our findings imply that hypoxia ADSC-isolated exosomes may represent as a valuable target for the treatment of diseases associated with lymphatic remodeling.