Exosomes from microRNA-199-3p-modified adipose-derived stem cells promote proliferation and migration of endothelial tip cells by downregulation of semaphorin 3A

Exosomes secreted by adipose-derived stem cells (ADSCs) have been shown to promote angiogenesis. This study aimed to investigate the effect of exosomes from ADSCs (ADSCs-Exos) on proliferation and migration of endothelial tip cells. In this study, ADSCs were analyzed by flow cytometry. The protein levels were examined by western blot. Cell proliferation and migration were assessed by CCK-8 assay, EdU cell proliferation assay and transwell migration assay. A luciferase reporter assay was performed to confirm whether sema3A was a direct target of miR-199a/b-3p. The results showed that ADSCs-Exos strikingly promoted the proliferation and migration of endothelial tip cells. The expression levels of miR-199a-3p and miR-199b-3p were strikingly increased in ADSCs and ADSCs-Exos. Compared to the Exos^scramble group, the proliferation and migration of endothelial tip cells was dramatically increased in the Exos^{199 mimic} group, but remarkably decreased in the Exos^{199 inhibitor} group. Moreover, Sema3A was a target of miR-199-3p. The stimulatory effects of Exos^{199 mimic} on the proliferation and migration of endothelial tip cells were negated by Sema3A overexpression. Besides, the expression of tissue inhibitor of metalloproteinase 3 (TIMP3) was decreased, and the expression of matrix metalloproteinases 9 (MMP9) and proliferating cell nuclear antigen (PCNA) were increased in endothelial tip cells co-cultured with ADSCs-Exos, which were substantially enhanced by Exos^{199 mimic} treatment. However, the effect of Exos^{199 mimic} on the protein expression of TIMP3, MMP9 and PCNA were negated by upregulation of Sema3A. In conclusion, exosomes from miR-199-3p-modified ADSCs promote proliferation and migration of endothelial tip cells by downregulation of sema3A.