Acellular cardiac scaffolds enriched with MSC-derived extracellular vesicles limit ventricular remodelling and exert local and systemic immunomodulation in a myocardial infarction porcine model
Monguió-Tortajada, Marta (Institut Germans Trias i Pujol)
Prat-Vidal, Cristina (Banc de Sang i Teixits)
Martínez-Falguera, Daina (Universitat de Barcelona)
Teis, Albert (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Soler-Botija, Carolina (Instituto de Salud Carlos III)
Courageux, Yvan (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Munizaga-Larroudé, Micaela (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Morón-Font, Miriam (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Bayés-Genís, Antoni (Universitat Autònoma de Barcelona. Departament de Medicina)
Borràs i Serres, Francesc Enric (Universitat de Barcelona. Departament de Biologia Cel·lular, Fisiologia i Immunologia)
Rudilla, F. (Institut d'Investigació Biomèdica de Bellvitge)
Gálvez-Montón, Carolina (Institut d'Investigació Biomèdica de Bellvitge)

Date:	2022
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.
Grants:	Fundació la Marató de TV3 201516-10 Agencia Estatal de Investigación PID-2019-110137RB-I00 Agencia Estatal de Investigación SAF2017-84324-C2-1-R Instituto de Salud Carlos III PI18/00256 Instituto de Salud Carlos III ICI19/00039 Instituto de Salud Carlos III ICI20/00135 Ministerio de Economía y Competitividad RD16/0011/0006 Ministerio de Economía y Competitividad CB16/11/00403 Instituto de Salud Carlos III PI21/01703 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-483 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-301
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Extracellular vesicles ; Cardiac fibrosis ; Ventricular remodeling ; Mesenchymal stromal/stem cells ; Myocardial infarction ; Swine/pig model ; Immunomodulation
Published in:	Theranostics, Vol. 12, Issue 10 (June 2022) , p. 4656-4670, ISSN 1838-7640

DOI: 10.7150/thno.72289
PMID: 35832072

15 p, 4.3 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Articles > Research articles
Articles > Published articles