Abstract 12303: Do Extracellular Vesicles Protect the Ischemic Myocardium Through the Proliferation of Pre-existing Cardiomyocytes?

IntroductionExtracellular Vesicles (EV) are cardioprotective through the transfer of their cargo to recipient cells and the subsequent activation of reparative pathways. We used a bi-transgenic fate-mapping MerCreMer/ZEG mouse model (80% GFP-labeled cardiomyocytes after tamoxifen induction) to asses...

Full description

Saved in:
Bibliographic Details
Published in:Circulation (New York, N.Y.) N.Y.), 2019-11, Vol.140 (Suppl_1 Suppl 1), p.A12303-A12303
Main Authors: Perotto, Maria, Lima Correa, Bruna, El Harane, Nadia, Desgres, Manon, Pidial, Laetitia, Bellamy, Valérie, Tence, Noémie, Baron, Emilie, Autret, Gwennhael, Guillas, Chloé, Kamaleswaran, Keirththana, Vilar, José, Renault, Nisa K, Gnecchi, Massimiliano, Silvestre, Jean-Sébastien, Menasché, Philippe
Format: Article
Language:English
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:IntroductionExtracellular Vesicles (EV) are cardioprotective through the transfer of their cargo to recipient cells and the subsequent activation of reparative pathways. We used a bi-transgenic fate-mapping MerCreMer/ZEG mouse model (80% GFP-labeled cardiomyocytes after tamoxifen induction) to assess whether one of these pathways involved de novo cardiogenesis.MethodsMyocardial infarction was induced in 60 MerCreMer/ZEG mice by permanent left anterior descending coronary artery ligation. Three weeks later, the surviving mice with a left ventricular ejection fraction (LVEF) ≤ 45% (n=30) received transcutaneous echo-guided injections in the peri-infarct myocardium of either EV (from 1.4x10 human iPSC-derived cardiovascular progenitor cells [CPC]; 10x10 particles; n=15) or PBS (n=15). Osmotic EdU pumps were implanted for 10-13 days to label the endogenous proliferation of cardiomyocytes. Four to six weeks after injection, mice were evaluated by echocardiography (n=15 per group) or MRI (n=6-7 per group) and hearts harvested for blinded transcriptomic (data pending), histological and immunological analyses.ResultsAfter 4-6 weeks, LV function and volumes were improved in EV-treated hearts. The echographic EF increased by 10% from baseline and this trend was confirmed by MRI (51.4±7% vs. 40.4±7% in controls; mean±SEM; p=0.05). However, the number of pre-existing cardiomyocytes (TnT/EdU/GFP) was modest and did not significantly differ between EV-treated hearts and controls, averaging 1.5% of the total cardiomyocyte content. Yet, EV treatment protected pre-existing cardiomyocytes in the border zone, as evidenced by a 5% increase of TnT/ WGA/ GFP cells compared to controls (32 sections/mice). EV delivery was associated with an infarct size reduction of 14.9%, a 2.5% decrease in fibrosis and an increased capillary density in the peri-infarct area compared to controls. Plasma immunoglobulin isotypes did not differ between groups.ConclusionsEV from iPSC-CPC improve cardiac function in mice with ischemic heart failure by mechanisms that do not seem to involve proliferation of pre-existing cardiomyocytes but are rather related to a mitigation of remodeling and inflammatory responses and an increase in angiogenesis.
ISSN:0009-7322
1524-4539
DOI:10.1161/circ.140.suppl_1.12303