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