Highly efficient magnetic labelling allows MRI tracking of the homing of stem cell‐derived extracellular vesicles following systemic delivery

Abstract

Human stem-cell-derived extracellular vesicles (EVs) are currently being investigated for cell-free therapy in regenerative medicine applications, but the lack of noninvasive imaging methods to track EV homing and uptake in injured tissues has limited the refinement and optimization of the approach. Here, we developed a new labelling strategy to prepare magnetic EVs (magneto-EVs) allowing sensitive yet specific MRI tracking of systemically injected therapeutic EVs. This new labelling strategy relies on the use of 'sticky' magnetic particles, namely superparamagnetic iron oxide (SPIO) nanoparticles coated with polyhistidine tags, to efficiently separate magneto-EVs from unencapsulated SPIO particles. Using this method, we prepared pluripotent stem cell (iPSC)-derived magneto-EVs and subsequently used MRI to track their homing in different animal models of kidney injury and myocardial ischemia. Our results showed that iPSC-derived EVs preferentially accumulated in the injury sites and conferred substantial protection. Our study paves a new pathway for preparing highly purified magnetic EVs and tracking them using MRI towards optimized, systemically administered EV-based cell-free therapies. K E Y WO R D S acute kidney injury, extracellular vesicle, iPSC, MRI, myocardial injury, stem cell This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Integrative biology of extracellular vesicles in diabetes mellitus and diabetic complications

“…Second, due to the complexity of EV contents, their functions, individually or collectively, are far from being fully elucidated. Many attempts have been made to address this issue, for e.g., by developing a single-vesicle array and imaging method to track EV uptake 513 , 514 . Third, limited information is available about the molecular mechanisms underlying the target specificity of EVs with different origins so far.…”

Mesenchymal Stem Cells Do Not Lose Direct Labels Including Iron Oxide Nanoparticles and DFO-89Zr Chelates through Secretion of Extracellular Vesicles

“…In a mouse study, Hu et al succeeded in labeling melanoma-derived EVs with SPION, and the labeled EVs were tracked using MRI for up to 48 h after injection [ 16 ]. A recent study reported by Han et al loaded SPION-coated with polyhistidine tags into pluripotent stem cell (iPSC)-derived EVs, which were shown to preferentially accumulate in the injury sites and conferred substantial protection [ 17 ]. The high efficacy of direct EV radiolabeling also has been reported recently [ 18 ].…”

Extracellular vesicles as a drug delivery system: A systematic review of preclinical studies

“…Recent theranostic platforms that allow imaging of therapeutic EVs harbor great potential to get a more precise understanding of their ways of action. Magnetic EVs, through loading of iron oxide nanoparticles, represent a sensitive and specific way of isolating EVs, enhancing tumor targeting under a magnetic field, and tracking systemically administered therapeutic EVs through magnetic particle imaging [109,138,307]. Another emerging strategy is the direct transfer of mitochondria [308][309][310] through EVs, which was recently reported to improve post-infarct cardiac function in vivo by restoring intracellular bioenergetics and mitochondrial biogenesis in the recipient cardiomyocytes [310].…”