Exosome-mimetic extracellular nanovesicles derived from iron oxide nanoparticles–incorporated mesenchymal stem cells for cardiac repair

Because of poor engraftment and safety concerns regarding mesenchymal stem cell (MSC) therapy, MSC-derived exosomes have emerged as an alternative cell-free therapy for myocardial infarction (MI). However, the diffusion of exosomes out of the infarcted heart following injection and the low productivity limit the potential of clinical applications.

Researchers from Seoul National University developed exosome-mimetic extracellular nanovesicles (NVs) derived from iron oxide nanoparticles (IONPs)–incorporated MSCs (IONP-MSCs). The retention of injected IONP-MSC–derived NVs (IONP-NVs) within the infarcted heart was markedly augmented by magnetic guidance. Furthermore, IONPs significantly increased the levels of therapeutic molecules in IONP-MSCs and IONP-NVs, which can reduce the concern of low exosome productivity. The injection of IONP-NVs into the infarcted heart and magnetic guidance induced an early shift from the inflammation phase to the reparative phase, reduced apoptosis and fibrosis, and enhanced angiogenesis and cardiac function recovery. This approach can enhance the therapeutic potency of an MSC-derived NV therapy.

Cellular uptake of IONPs and IONP-triggered cellular modification

(A) Schematic illustration and TEM image of IONPs. PEG, polyethylene glycol. (B) Fluorescent images of IONP (red) uptake by MSCs 24 hours after IONP treatment [green, cell membrane; and blue, 4′,6-diamidino-2-phenylindole (DAPI)]. Scale bars, 100 μm. (C) The cytotoxicity of IONPs 2, 4, 7, 10, and 14 days after IONP treatment to MSCs, as evaluated by CCK assay (n = 4 per group; NS, no significant difference). (D) Relative mRNA expression levels of various cardiac repair–favorable genes in MSC and IONP-MSC, as evaluated by qRT-PCR (n = 4 per group). (E) Schematic illustration of the IONP-mediated intracellular signaling cascades in MSCs and Western blot analysis for the intracellular signaling cascade molecules and associated therapeutic molecules (n= 3 per group). *P < 0.05 by two-tailed t test. All values are means ± SD.

Ju-Ro Lee, Bong-Woo Park, Jonghoon Kim, Yeon Woong Choo, Han Young Kim, Jeong-Kee Yoon, Hyeok Kim, Ji-Won Hwang, Mikyung Kang, Sung Pil Kwon, Seuk Young Song, In Ok Ko, Ji-Ae Park, Kiwon Ban, Taeghwan Hyeon, Hun-Jun Park, Byung-Soo Kim. (2020) Nanovesicles derived from iron oxide nanoparticles–incorporated mesenchymal stem cells for cardiac repair. Sci Adv 6(18);eaaz0952. [article]

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