How can extracellular vesicles that mediate cardiovascular disease be decreased?

Strategies to Decrease Extracellular Vesicles That Mediate Cardiovascular Disease

Stem cell-derived extracellular vesicles (EVs) offer the most promising approach to decrease pathological EVs that mediate cardiovascular disease by providing cardioprotective, pro-angiogenic, and anti-inflammatory effects. 1

Understanding Extracellular Vesicles in Cardiovascular Disease

Extracellular vesicles are membrane-enclosed structures released by nearly all cell types that play crucial roles in:

• Transporting regulatory molecules (RNA species, lipids, proteins) through extracellular spaces and delivering these cargos to recipient cells 1
• Mediating cell-to-cell communication in both physiological and pathological cardiovascular processes 2
• Powerfully stimulating angiogenesis and protecting the heart against myocardial infarction 1

Therapeutic Approaches to Decrease Pathological EVs

1. Stem Cell-Derived EVs

Mesenchymal stromal cells (MSCs) represent the most studied cell population for therapeutic EV production:

• MSC-derived EVs have demonstrated reduced infarct size in both murine and porcine models 1
• The exosome-containing fraction decreases oxidative stress and activates the PI3K/Akt pathway in the myocardium 1
• MSCs produce multiple subtypes of EVs with different biogenesis pathways and functions 1

2. Cardiac-Derived Progenitor Cell EVs

• Cardiac progenitor cell (CPC) EVs exhibit cardioprotective and pro-angiogenic effects 1
• These effects are partly mediated via extracellular matrix metalloproteinase inducer (EMMPRIN) 1
• CPC-derived EVs contain enriched miRNA clusters important for their therapeutic effects 1

3. Other Cell-Derived EVs with Therapeutic Potential

• Blood-outgrowth endothelial cells and circulating CD34+ stem cells produce EVs with pro-angiogenic activity 1
• Endothelial cell-derived EVs can suppress monocyte activation 1
• Regulatory T cell (Treg) EVs exert immune-suppressive functions 1
• Mouse embryonic stem cell exosomes augment neovascularization, myocyte proliferation, and survival after myocardial infarction 1

4. Hybrid Nanomedicine Approaches

• Loading EVs with therapeutic molecules (siRNA, proteins, small molecules) for targeted drug delivery 1
• Liposomes with phospholipid bilayers can carry various proteins, nucleic acids, and pharmaceutically active substances to injured heart tissue 1
• Exosome-mimetic structures with specific targeting molecules enhance delivery to target tissues 1
• These approaches offer advantages of being more controllable and scalable for clinical settings 1

Administration Routes and Pharmacokinetics

• Intramyocardial delivery of MSC-derived EVs has shown effectiveness in pigs, while intracoronary delivery was not effective post-reperfusion 1
• EVs are rapidly cleared from circulation with a half-life of approximately 2-4 minutes 1
• Surface molecules such as phospholipids and proteins determine pharmacokinetics and cellular uptake 1
• High concentrations of intravenous EVs should be approached with caution, as rapid asphyxiation has been observed in mice when injecting over 400 mg 1

Limitations and Challenges

Several important limitations must be overcome before EVs can enter clinical practice 1:

• Therapeutic differences observed among comparable EV fractions due to donor variability or EV heterogeneity 1
• Purification challenges, including potential heterogeneity of EVs and presence of co-purified molecules 1
• Lack of standardized quality control methods for EV production 1
• Unknown pharmacokinetics requiring detailed follow-up to understand bio-distribution 1
• Potential immunogenicity concerns with non-autologous EVs 1
• Need for industrial-scale, reproducible methods of isolating GMP-quality EVs 1

Future Directions

To advance EV therapeutics for cardiovascular disease, several developments are needed 1:

• Improvement of isolation methods and standardization of analytical procedures 1
• Development of novel high-resolution methodologies for EV isolation and visualization 1
• Better understanding of mechanisms of inter-cell or inter-organ communication 1
• Exploration of EVs as cardiac-specific therapeutic packages 1
• Leveraging the multi-targeting effects of EVs for complex mechanisms of ischemic heart disease 1

Clinical Implications

When considering EV-based therapies for cardiovascular disease, clinicians should note:

• EVs provide several advantages over cell therapies, including absence of tumorigenicity, conservation of activity between species, and lower immunogenic potential 1
• The ideal route of administration appears to be intramyocardial rather than intracoronary delivery 1
• The therapeutic effects of EVs include cardioprotection, angiogenesis, and anti-inflammatory actions 1
• Plasma EVs themselves have shown ability to protect the myocardium from ischemia and reperfusion injury 1