Key Points: BMSCs and MM cells mutually communicate through exosomes, which carry selective cytokines. BMSC-derived exosomes favor MM cell proliferation, migration, and survival and induce drug resistance to bortezomib.

Atherosclerosis is a chronic inflammatory disease caused mainly by lipid accumulation and excessive inflammatory immune response. Although the lipid-lowering and cardioprotective properties of bilirubin, as well as the negative relationship between bilirubin and atherosclerosis, were well documented, it is not yet clear whether bilirubin can attenuate atherosclerosis in vivo. In this study, we investigated the role of bilirubin in improving atherosclerosis. We found that mildly elevated bilirubin significantly reduced the risk factors of atherosclerosis, such as plasma glucose, total cholesterol, and low-density lipoprotein cholesterol, and the formation of atherosclerotic plaques, liver total cholesterol, and cholesterol ester concentration in apolipoprotein E-deficient (ApoE^−/−) mice fed a western-type (high fat) diet. It was further found that bilirubin could promote the degradation of 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), a rate-limiting enzyme for endogenous cholesterol synthesis. Using mass cytometry-based high dimensional single cell analysis, we observed a decrease of natural killer cells and an increase of dendritic cells and myeloid-derived suppressor cells, which all are closely associated with atherosclerosis risk factors and contribute to the improvement of atherosclerosis, in ApoE^−/− mice treated with bilirubin. By in-depth analysis, modulation of multiple spleen or peripheral blood T cell clusters exhibiting either positive or negative correlations with total cholesterol or low-density lipoprotein cholesterol was detected after bilirubin treatment. In this study, we demonstrate that bilirubin serves as a negative regulator of atherosclerosis and reduces atherosclerosis by inhibiting cholesterol synthesis and modulating the immune system.

Drug resistance, difficulty in specific targeting and self-renewal properties of cancer stem cells (CSCs) all contribute to cancer treatment failure and relapse. CSCs have been suggested as both the seeds of the primary cancer, and the roots of chemo- and radio-therapy resistance. The ability to precisely deliver drugs to target CSCs is an urgent need for cancer therapy, with nanotechnology-based drug delivery system being one of the most promising tools to achieve this in the clinic. Exosomes are cell-derived natural nanometric vesicles that are widely distributed in body fluids and involved in multiple disease processes, including tumorigenesis. Exosome-based nanometric vehicles have a number of advantages: they are non-toxic, non-immunogenic, and can be engineered to have robust delivery capacity and targeting specificity. This enables exosomes as a powerful nanocarrier to deliver anti-cancer drugs and genes for CSC targeting therapy. Here, we will introduce the current explorations of exosome-based delivery system in cancer therapy, with particular focus on several exosomal engineering approaches that have improved their efficiency and specificity for CSC targeting.

The bone marrow microenvironment enhances multiple myeloma progression by exosome-mediated activation of myeloid-derived suppressor cells