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The MSC-EV-microRNAome: A Perspective on Therapeutic Mechanisms of Action in Sepsis and ARDS
Claudia C Dos Santos1,2, Miquéias Lopes-Pacheco3,4, Karen English5,6
1Institute of Medical Sciences and Interdepartmental Division of Critical Care, Department of Medicine, University of Toronto, Toronto, ON M5B 1T8, Canada.
Abstract:
Mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (EVs) have emerged as innovative therapeutic agents for the treatment of sepsis and acute respiratory distress syndrome (ARDS). Although their potential remains undisputed in pre-clinical models, this has yet to be translated to the clinic. In this review, we focused on the role of microRNAs contained in MSC-derived EVs, the EV microRNAome, and their potential contribution to therapeutic mechanisms of action. The evidence that miRNA transfer in MSC-derived EVs has a role in the overall therapeutic effects is compelling. However, several questions remain regarding how to reconcile the stochiometric issue of the low copy numbers of the miRNAs present in the EV particles, how different miRNAs delivered simultaneously interact with their targets within recipient cells, and the best miRNA or combination of miRNAs to use as therapy, potency markers, and biomarkers of efficacy in the clinic. Here, we offer a molecular genetics and systems biology perspective on the function of EV microRNAs, their contribution to mechanisms of action, and their therapeutic potential.
Insights
Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) show therapeutic promise for sepsis and ARDS. This review explores the role of microRNAs within these EVs, addressing challenges for clinical translation.
Area of Science:
- Biomedical Sciences
- Regenerative Medicine
- Molecular Biology
Background:
- Mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs) are promising therapeutics for sepsis and acute respiratory distress syndrome (ARDS).
- Clinical translation of MSC- and EV-based therapies is hindered by a lack of mechanistic understanding.
Purpose of the Study:
- To review the role of microRNAs (miRNAs) within MSC-derived EVs (the EV microRNAome) in therapeutic mechanisms.
- To identify key questions and challenges for the clinical application of EV-based miRNA therapeutics.
Main Methods:
- Literature review focusing on molecular genetics and systems biology perspectives.
- Analysis of the contribution of EV microRNAs to therapeutic effects in pre-clinical models.
Main Results:
- Evidence strongly supports miRNA transfer via MSC-derived EVs as a key therapeutic mechanism.
- Significant challenges remain, including miRNA stoichiometry, multi-miRNA interactions, and identification of optimal therapeutic miRNA combinations and biomarkers.
Conclusions:
- EV microRNAs are critical for the therapeutic potential of MSC-derived EVs.
- Further research is needed to address mechanistic and translational challenges for clinical application.
