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Theranostics 2022; 12(10):4656-4670. doi:10.7150/thno.72289 This issue Cite

Research Paper

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

Marta Monguió-Tortajada^1,2, Cristina Prat-Vidal^1,3, Daina Martínez-Falguera^1,4, Albert Teis², Carolina Soler-Botija^1,5, Yvan Courageux^1,6, Micaela Munizaga-Larroudé¹, Miriam Moron-Font⁷, Antoni Bayes-Genis^1,2,5,8, Francesc E. Borràs^7,9, Santiago Roura^{1,2,5,10,11✉}, Carolina Gálvez-Montón^1,2,5,11✉

1. ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain.
2. Heart Institute (iCor), Cardiology Department, Germans Trias i Pujol University Hospital, Badalona, Spain.
3. Cell Therapy Service, Banc de Sang i Teixits (BST), Barcelona, Spain.
4. Faculty of Medicine, Universitat de Barcelona (UB), Barcelona, Spain.
5. CIBERCV, Instituto de Salud Carlos III, Madrid, Spain.
6. Department of Biochemistry, Molecular Biology and Biomedicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
7. REMAR-IVECAT Group, Health Science Research Institute Germans Trias i Pujol and Nephrology Service, Germans Trias i Pujol University Hospital, Can Ruti Campus, Badalona, Spain.
8. Department of Medicine, UAB, Barcelona, Spain.
9. Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, Spain.
10. Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), Vic, Barcelona 08500, Spain.
11. Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, L´Hospitalet de Llobregat, Spain.

✉ Corresponding authors: Dr Santiago Roura, E-mail: srouracat; Dr Carolina Gálvez-Montón, E-mail: cgalvezcat.

Abstract

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.

Keywords: extracellular vesicles, cardiac fibrosis, ventricular remodeling, mesenchymal stromal/stem cells, myocardial infarction, swine/pig model, immunomodulation

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