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Metabolically-engineered MSC-derived Exosomes – A New Treatment for Rheumatoid Arthritis

Review of "Metabolically engineered stem cell-derived exosomes to regulate macrophage heterogeneity in rheumatoid arthritis" from Science Advances by Stuart P. Atkinson

Mesenchymal stem cell (MSC)-derived exosomes represent a potentially exciting treatment for autoimmune diseases in general [1] and rheumatoid arthritis in particular by inducing pro-inflammatory M1 to anti-inflammatory M2 macrophage polarization within inflamed tissue [2]. Notably, the accumulation of exosomes in and their removal by the liver and spleen [3, 4] and their resultant short biological half-lives [5] have prompted the development of exosome surface engineering strategies to avoid these limitations [6].

Unfortunately, many of these strategies do not strictly apply to MSC-derived exosomes; therefore, researchers led by Jae Hyung Park (Sungkyunkwan University, Suwon, South Korea) explored the potential of metabolic glycoengineering of adipose-derived MSCs and their enhanced isolation to generate surface-modified exosomes that efficiently target M1 macrophages in the inflamed joints of a rheumatoid arthritis model [7].

You and Lim et al. first modified the MSC surface via metabolic glycoengineering-mediated click chemistry to carry a modified-dextran sulfate ligand as a targeting moiety for macrophage scavenger receptor class A, which is abundant within inflamed joints [8]. The authors then confirmed that exosomes generated by modified MSCs also carried the macrophage-targeting ligand following their isolation by tangential flow filtration from the conditioned medium (used without an additional complicated purification step). Comparisons with conventionally-modified exosomes highlighted that engineered exosomes displayed greater stability, higher amounts of protein, and improved yields while also carrying cargoes of microRNAs known to promote M2 macrophage polarization.

Engineered exosomes also displayed enhanced targeting of inflammatory-macrophages in vitro, improving M2 macrophage polarization efficacy and significantly inhibiting M1 macrophage polarization through the activity let-7b-5p and miR-24-3p miRNAs. In vivo analyses also established that engineered exosomes robustly targeted the inflamed joints of arthritic mice following systemic administration, where they induced an enhanced therapeutic effect as evidenced by improved clinical scores, paw thickness, bone density scores, and imaging of inflamed joints and the reduction in levels of cartilage erosion, neutrophil infiltration, and synovial inflammation. Importantly, the authors linked the efficient reprogramming of the synovial microenvironment of the inflamed joints to the regulation of macrophage heterogeneity.

Overall, the authors anticipate that these findings will support the ongoing development of this strategy to include other stem cell types and a broader range of tissue/cell-targeting moieties. Furthermore, they foresee that the regulation of macrophage heterogeneity using the strategy described in this article may improve treatments for other inflammatory macrophage-associated diseases, such as inflammatory bowel disease, idiopathic pulmonary fibrosis, atherosclerosis, and Alzheimer's disease.

For more on metabolic engineering, MSC-derived exosomes, and associated enhanced therapeutic advances, stay tuned to the Stem Cells Portal!


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