期刊
THERANOSTICS
卷 12, 期 10, 页码 4656-4670出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.72289
关键词
extracellular vesicles; cardiac fibrosis; ventricular remodeling; mesenchymal stromal; stem cells; myocardial infarction; swine; pig model; immunomodulation
资金
- Fundacio La Marato de TV3 [201516-10]
- MICINN [PID-2019-110137RB-I00, SAF2017-84324-C2-1-R]
- Instituto de Salud Carlos III [PI18/00256, ICI19/00039, ICI20/00135, RD16/0011/0006, CB16/11/00403, PI21/01703]
- AGAUR Generalitat de Catalunya [2017-SGR-483, 2017-SGR-301]
- Societat Catalana de Cardiologia
- Institut Catala de Salut
- Red RICORS [PI21/01703]
- ISCIII-Subdireccion General de Evaluacion y el Fondo Europeo de Desarrollo Regional (FEDER)
This study demonstrates the preclinical efficacy of locally delivering cATMSC-EV in an acute myocardial infarction (MI) pig model, showing improved cardiac function and reduced myocardial remodeling.
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 TNF alpha 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.
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