Apoptotic bodies derived from human umbilical cord mesenchymal stem cells improve recovery from myocardial infarction in swine.

Summary

In a porcine MI model, umbilical cord MSC-derived apoptotic bodies improved contractility, reduced infarct size, and limited adverse remodeling, paralleling MSCs. Mechanistically, ABs activated AMPK and modulated TFEB to regulate autophagy; let-7f-5p targeting PPP2R2A and MAP4K3 contributed to these effects.

Key Findings

• In vitro, ABs reduced apoptosis and cytotoxicity in OGD-stressed cardiomyocytes and enhanced endothelial migration and tube formation.
• In vivo in pigs with MI, ABs improved contractile function, reduced infarct size, and mitigated adverse remodeling with increased cardiomyocyte survival and angiogenesis.
• Cardioprotection was mediated by autophagy regulation via AMPK activation and TFEB modulation.
• let-7f-5p was the most abundant microRNA in ABs and promoted AMPK phosphorylation (targeting PPP2R2A) and decreased TFEB phosphorylation (targeting MAP4K3).

Clinical Implications

MSC-derived apoptotic bodies could serve as an off-the-shelf, acellular therapy for MI, potentially reducing risks of cell engraftment and immunologic complications. The AMPK/TFEB-autophagy axis and let-7f-5p targets offer biomarkers and druggable nodes for translation.

Limitations

• Preclinical study; durability, dosing, and immunogenicity of ABs in humans remain undefined
• Standardization and scalability of AB isolation/characterization require further development

Future Directions

Define AB manufacturing standards, dose-response, and safety in GLP studies; evaluate biomarkers (let-7f-5p, AMPK/TFEB signaling) and initiate phase 1 trials in post-MI patients.