Theranostics 2021; 11(20):10114-10124. doi:10.7150/thno.62304 This issue Cite

Research Paper

Extracellular vesicles fail to trigger the generation of new cardiomyocytes in chronically infarcted hearts

Bruna Lima Correa1*, Nadia El Harane2*, Manon Desgres1, Maria Perotto3, Paul Alayrac1, Chloé Guillas1, Laetitia Pidial1, Valérie Bellamy1, Emilie Baron4, Gwennhael Autret1, Keirththana Kamaleswaran1, Chloé Pezzana1, Marie-Cécile Perier1, José Vilar1, Antonio Alberdi5, Alain Brisson6, Nisa Renault7, Massimiliano Gnecchi3, Jean-Sébastien Silvestre1, Philippe Menasché1,8✉

1. Université de Paris, PARCC, Inserm, F-75015 Paris, France.
2. University of Geneva, Translational Research Centre in Onco-hematology, Department of Medicine, Geneva, Switzerland.
3. Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy and Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
4. Department of Cardiology, Hôpital Européen Georges Pompidou, F-75015 Paris, France.
5. Inserm, UMRS-976, Hôpital Saint-Louis, Paris, France.
6. UMR-CBMN, Université de Bordeaux, CNRS, IPB, F-33600 Pessac, France.
7. Fujifilm Cellular Dynamics, Inc, Madison, Wisconsin, USA.
8. Department of Cardiovascular Surgery, Hôpital Européen Georges Pompidou, F-75015 Paris, France.
* Equal contribution

Citation:
Lima Correa B, El Harane N, Desgres M, Perotto M, Alayrac P, Guillas C, Pidial L, Bellamy V, Baron E, Autret G, Kamaleswaran K, Pezzana C, Perier MC, Vilar J, Alberdi A, Brisson A, Renault N, Gnecchi M, Silvestre JS, Menasché P. Extracellular vesicles fail to trigger the generation of new cardiomyocytes in chronically infarcted hearts. Theranostics 2021; 11(20):10114-10124. doi:10.7150/thno.62304. https://www.thno.org/v11p10114.htm
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Abstract

Graphic abstract

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.


Citation styles

APA
Lima Correa, B., El Harane, N., Desgres, M., Perotto, M., Alayrac, P., Guillas, C., Pidial, L., Bellamy, V., Baron, E., Autret, G., Kamaleswaran, K., Pezzana, C., Perier, M.C., Vilar, J., Alberdi, A., Brisson, A., Renault, N., Gnecchi, M., Silvestre, J.S., Menasché, P. (2021). Extracellular vesicles fail to trigger the generation of new cardiomyocytes in chronically infarcted hearts. Theranostics, 11(20), 10114-10124. https://doi.org/10.7150/thno.62304.

ACS
Lima Correa, B.; El Harane, N.; Desgres, M.; Perotto, M.; Alayrac, P.; Guillas, C.; Pidial, L.; Bellamy, V.; Baron, E.; Autret, G.; Kamaleswaran, K.; Pezzana, C.; Perier, M.C.; Vilar, J.; Alberdi, A.; Brisson, A.; Renault, N.; Gnecchi, M.; Silvestre, J.S.; Menasché, P. Extracellular vesicles fail to trigger the generation of new cardiomyocytes in chronically infarcted hearts. Theranostics 2021, 11 (20), 10114-10124. DOI: 10.7150/thno.62304.

NLM
Lima Correa B, El Harane N, Desgres M, Perotto M, Alayrac P, Guillas C, Pidial L, Bellamy V, Baron E, Autret G, Kamaleswaran K, Pezzana C, Perier MC, Vilar J, Alberdi A, Brisson A, Renault N, Gnecchi M, Silvestre JS, Menasché P. Extracellular vesicles fail to trigger the generation of new cardiomyocytes in chronically infarcted hearts. Theranostics 2021; 11(20):10114-10124. doi:10.7150/thno.62304. https://www.thno.org/v11p10114.htm

CSE
Lima Correa B, El Harane N, Desgres M, Perotto M, Alayrac P, Guillas C, Pidial L, Bellamy V, Baron E, Autret G, Kamaleswaran K, Pezzana C, Perier MC, Vilar J, Alberdi A, Brisson A, Renault N, Gnecchi M, Silvestre JS, Menasché P. 2021. Extracellular vesicles fail to trigger the generation of new cardiomyocytes in chronically infarcted hearts. Theranostics. 11(20):10114-10124.

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