Journal Article

Extracellular vesicles from human iPS-derived cardiovascular progenitor cells stimulate the proliferation of cardiomyocytes in the injured heart

Correa, Bruna Lima, El Harane, Nadia, Perotto, Maria L, Woolaver, Eliwabeth, Pidial, Laetitia, Kervadec, Anaïs L, Bellamy, Valérie L, Zlatanova, Ivana, Ifergan, Gabriel, Renault, Nisa L, Nematalla, Hany, Silvestre, Jean-Sébastien, Menasché, Philippe

2018

Overview

Background: Extracellular vesicles (EV) seem to mediate the benefits of cell therapy for ischaemic heart failure but their mechanism of action remains poorly understood. The doubly transgenic fate-mapping MerCreMer/ZEG mice model allows to distinguish whether new cardiomyocytes originate from the division of preexisting ones (GFP+, Troponin [TnT+]) or have differentiated from endogenous progenitors, in which case they stain positive for Lac Z and TnT but negative for GFP. Methods: Myocardial infarction was induced in 12 MerCreMer/ZEG mice by permanent occlusion of the left anterior descending coronary artery. Three weeks later, the surviving mice with a left ventricular ejection fraction (LVEF) <45% received transcutaneous echo-guided injections in the peri-infarct myocardium of EV from 1.4 x 106 human iPS-derived cardiovascular progenitor cells (hiPS-CPg-derived EV) (hiPS-Pg; 10 x 109, n = 6) or PBS (n = 6). Seven days later, four mice (two in each group) were sacrificed for histological assessment. The remaining mice were blindly evaluated by echocardiography 6 weeks after injections, and their hearts were also processed for histology. In parallel, in vitro assays were developed to determine if fluorescently labelled EV were internalized in cultured rat cardiomyocytes. Results: Seven days after EV injection, there was an average of 35 ± 10 cardiomyocytes in the infarcted area of the two treated hearts, which stained positive for TnT and LacZ but negative for GFP, suggesting that they differentiated from endogenous progenitors. Conversely, no TnT+ cardiomyocytes were identified in the scar of PBS-injected hearts. Six weeks after injections, cardiac function was only improved in the EV-treated hearts (n = 4), as evidenced by decreased LV volumes and increased LVEF (+16%) relative to baseline. In vitro, EV were internalized by CM and the transfer of their miRNA and protein payload was demonstrated by a positive intracellular staining for labels specific for these moieties. Summary/Conclusion: hiPS-CPg-derived EV improve the function of chronically infarcted hearts, possibly, in parts, through EV-mediated miR and protein transfer fostering generation of new cardiomyocytes from endogenous sources.

• Publisher: John Wiley & Sons, Inc
• Subject: Calcium-binding protein / Cardiomyocytes / Cell fate / Cell proliferation / Coronary artery / Echocardiography / Extracellular vesicles / Fate maps / Heart diseases / Hip / miRNA / Myocardial infarction / Myocardium / Occlusion / Progenitor cells / Stem cells / Transgenic mice / Troponin / Ventricle