Open AccessExtracellular vesicles fail to trigger the generation of new cardiomyocytes in chronically infarcted hearts
Author(s) -
Bruna Lima Correa,
Nadia El Harane,
Ma Desgres,
Maria Perotto,
Paul Alayrac,
Chloé Guillas,
Laetitia Pidial,
Valérie Bellamy,
Émilie Baron,
Gwennhaël Autret,
Keirththana Kamaleswaran,
Chloé Pezzana,
MarieCécile Perier,
José Vilar,
A. Alberdi,
Alain Brisson,
Nicolas Renault,
Massimiliano Gnecchi,
JeanSébastien Silvestre,
Philippe Menasché
Publication year - 2021
Publication title -
theranostics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.689
H-Index - 97
ISSN - 1838-7640
DOI - 10.7150/thno.62304
Subject(s) - ejection fraction , cardiac function curve , endogeny , progenitor cell , genetically modified mouse , medicine , regeneration (biology) , ligation , myocyte , myocardial infarction , transgene , cardiology , stem cell , heart failure , microbiology and biotechnology , chemistry , biology , biochemistry , gene
Background: Extracellular vesicles (EV) mediate the therapeutic effects of stem cells but it is unclear whether this involves cardiac regeneration mediated by endogenous cardiomyocyte proliferation. Methods: Bi-transgenic MerCreMer/ZEG (n = 15/group) and Mosaic Analysis With Double Markers (MADM; n = 6/group) mouse models underwent permanent coronary artery ligation and received, 3 weeks later, 10 billion EV (from human iPS-derived cardiovascular progenitor cells [CPC]), or saline, injected percutaneously under echo guidance in the peri-infarcted myocardium. Endogenous cardiomyocyte proliferation was tracked by EdU labeling and biphoton microscopy. Other end points, including cardiac function (echocardiography and MRI), histology and transcriptomics were blindly assessed 4-6 weeks after injections. Results: There was no proliferation of cardiomyocytes in either transgenic mouse strains. Nevertheless, EV improved cardiac function in both models. In MerCreMer/ZEG mice, LVEF increased by 18.3 ± 0.2% between baseline and the end-study time point in EV-treated hearts which contrasted with a decrease by 2.3 ± 0.2% in the PBS group; MADM mice featured a similar pattern as intra-myocardial administration of EV improved LVEF by 13.3 ± 0.16% from baseline whereas it decreased by 14.4 ± 0.16% in the control PBS-injected group. This functional improvement was confirmed by MRI and associated with a reduction in infarct size, the decreased expression of several pro-fibrotic genes and an overexpression of the anti-fibrotic miRNA 133-a1 compared to controls. Experiments with an anti-miR133-a demonstrated that the cardio-reparative effects of EV were partly abrogated. Conclusions: EV-CPC do not trigger cardiomyocyte proliferation but still improve cardiac function by other mechanisms which may include the regulation of fibrosis.