Replenishing exosomes from older bone marrow stromal cells with miR-340 inhibits myeloma-related angiogenesis

The study of bone marrow stromal cells (BMSCs) and the exosomes they secrete is considered promising for cancer therapy. However, little is known about the effect of donor age on BMSCs. In the present study, we investigated the therapeutic potential of BMSC exosomes derived from donors of different ages using an in vivo model of hypoxic bone marrow in multiple myeloma (MM). We found that donor age was strongly related to senescent changes in BMSCs. Exosomes derived from young BMSCs significantly inhibited MM-induced angiogenesis in Matrigel plugs. The exosomal microRNA (miRNA) expression profile was different between young and older BMSCs, despite similarities in the size and quantity of exosomes. Of note was the observation that the antiangiogenic effect of older BMSCs was enhanced by direct transfection of miR-340 that was preferentially expressed in exosomes derived from young BMSCs. We found that miR-340 inhibited angiogenesis via the hepatocyte growth factor/c-MET (HGF/c-MET) signaling pathway in endothelial cells. Our data provide new insights into exosome-based cancer therapy by modification of BMSC-derived exosomes.