Acellular cardiac scaffolds enriched with MSC-derived extracellular vesicles limit ventricular remodelling and exert local and systemic immunomodulation in a myocardial infarction porcine model

• Published in: Theranostics Vol. 12; no. 10; pp. 4656 - 4670
• Main Authors: Monguió-Tortajada, Marta, Prat-Vidal, Cristina, Martínez-Falguera, Daina, Teis, Albert, Soler-Botija, Carolina, Courageux, Yvan, Munizaga-Larroudé, Micaela, Moron-Font, Miriam, Bayes-Genis, Antoni, Borràs, Francesc E., Roura, Santiago, Gálvez-Montón, Carolina
• Format: Journal Article
• Language: English
• Published: Wyoming Ivyspring International Publisher Pty Ltd 01.01.2022; Ivyspring International Publisher
• Subjects: Extracellular vesicles; Females; Fentanyl; Heart attacks; Heart surgery; Hogs; Hydrogels; Infrared imaging systems; Ischemia; Labeling; Laboratory animals; Magnetic resonance imaging; Medical research; Ostomy; Peptides; Research Paper; Sucrose; Tissue engineering
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.72289

Rationale: Extracellular vesicles (EVs) from mesenchymal stromal cell (MSC) are a potential therapy for cardiac healing after myocardial infarction (MI). Nevertheless, neither their efficient administration nor therapeutic mechanisms are fully elucidated. Here, we evaluate the preclinical efficacy of a tissue engineering approach to locally deliver porcine cardiac adipose tissue MSC-EV (cATMSC-EV) in an acute MI pig model.Methods: After MI by permanent ligation of the coronary artery, pigs (n = 24) were randomized to Untreated or treated groups with a decellularised pericardial scaffold filled with peptide hydrogel and cATMSC-EV purified by size exclusion chromatography (EV-Treated group) or buffer (Control group), placed over the post-infarcted myocardium.Results: After 30 days, cardiac MRI showed an improved cardiac function in EV-Treated animals, with significantly higher right ventricle ejection fraction (+20.8% in EV-Treated; p = 0.026), and less ventricle dilatation, indicating less myocardial remodelling. Scar size was reduced, with less fibrosis in the distal myocardium (-42.6% Col I in EV-Treated vs Untreated; p = 0.03), a 2-fold increase in vascular density (EV-Treated; p = 0.019) and less CCL2 transcription in the infarct core. EV-treated animals had less macrophage infiltration in the infarct core (-31.7% of CD163+ cells/field in EV-Treated; p = 0.026), but 5.8 times more expressing anti-inflammatory CD73 (p = 0.015). Systemically, locally delivered cATMSC-EV also triggered a systemic effect, doubling the circulating IL-1ra (p = 0.01), and reducing the PBMC rush 2d post-MI, the TNFα and GM-CSF levels at 30d post-MI, and modulating the CD73+ and CCR2+ monocyte populations, related to immunomodulation and fibrosis modulation.Conclusions: These results highlight the potential of cATMSC-EV in modulating hallmarks of ischemic injury for cardiac repair after MI.