Delivery of vascular endothelial growth factor (VEGFC) via engineered exosomes improves lymphedema

BACKGROUND: Lymphedema is a chronic disease results from impaired flow of the lymphatic system. Therefore, reconstruction of lymphatic system is crucial to treat limb lymphedema. Vascular endothelial growth factor (VEGFC) has been reported to be an important regulator involved in the growth and differentiation of lymphatic endothelial cells; however; the application of exosomes with VEGFC in the treatment of lymphedema has been rarely reported. METHODS: From the membrane-based fusion technology, we constructed engineered exosomes that overexpress CD63-VEGFC fusion protein (CD63-VEGFC/exos). We examined the in vitro effects of CD63-VEGFC/exos on the proliferation, migration, and tube formation of human dermal lymphatic endothelial cells (HDLECs) by MTT assay, migration assay, and tube formation assay, respectively. CD63-VEGFC/exos were embedded in sodium alginate hydrogel and their effect on lymphedema was evaluated by a mouse model. RESULTS: VEGFC could be successfully delivered to lymphatic endothelial cells via engineered CD63-VEGFC/exos. Treatment with CD63-VEGFC/exos resulted in a significant increase in the proliferation, migration, and tube formation of lymphatic endothelial cells. Using CD63-VEGFC/egos in sodium alginate hydrogel enabled a sequenced release of exosomes and markedly improved lymphedema in a mouse model. CONCLUSIONS: Our findings supply a novel adipose tissue-derived stem cell (ADSC)-exo-based strategy that delivers target proteins to lymphatic endothelial cells and thus enhances the treatment of lymphedema.