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Table 7 Challenges for clinical application of MSC-derived EV therapy for renal disease

From: Mesenchymal stem cell-derived extracellular vesicles for kidney repair: current status and looming challenges

Challenges Explanation Future directions
EV source, isolation, and storage • MSCs derived from different sources may release EVs with distinct content and regenerative effects
• EV isolation and storage methods may potentially affect EV characteristics
• Compare the renoprotective properties of EVs released from different MSC sources
• Methods for EV isolation and storage for future clinical studies
Heterogeneity of EV subpopulations • Exosomes and microvesicles may exert distinct renoprotective properties • Determine which EV subpopulations show superior regenerative potential in patients with renal disease
Plasticity of EV cargo • Modulation of ex vivo culture conditions might alter the transcriptional and protein signatures of EVs and potentiate their renoprotective effects • Identify optimal preconditioning maneuvers
Effect of cardiovascular risk factors on EVs • Cardiovascular comorbidities are common among patients with renal disease and may limit their regenerative potential
• May limit autologous use
• Determine the efficacy of MSC-derived EVs in patients with comorbidities
Fate and engraftment • Relatively small amounts of EVs are detected in the kidneys after systemic administration
• Current detection methods often fail to identify engraftment into renal cell types and monitor the fate of MSC-derived EVs, possibly due to their small size
• Unlike MSCs, EVs cannot proliferate
• Might be promptly removed by immune cells
• Need to develop tools to target EVs to the kidneys
• Need methods to better assess engraftment, survival, and function of MSC-derived EVs
Safety and long-term effects • EVs modulate the transcriptional and translational machinery of recipient cells
• Although MSCs are generally safe, long-term benefits and side effects of exogenous EVs have not been adequately explored
• Explore MSC-derived EVs long-term benefits and potential side effects in patients with renal disease
Delivery regimens • Dose–response relation and optimal intervals between multiple doses of EVs have not been studied in treatment of renal diseases
• The best route of delivery might be invasive (intrarenal)
• Future preclinical and clinical studies are needed to define optimal dose regimen in these patients
• Development of kidney-targeted EVs may facilitate systemic delivery