MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs
Open accessAbstract
Prompt coronary catheterization and revascularization have markedly improved the outcomes of myocardial infarction, but have also resulted in a growing number of surviving patients with permanent structural damage of the heart, which frequently leads to heart failure. There is an unmet clinical need for treatments for this condition 1, particularly given the inability of cardiomyocytes to replicate and thereby regenerate the lost contractile tissue 2. Here we show that expression of human microRNA-199a in infarcted pig hearts can stimulate cardiac repair. One month after myocardial infarction and delivery of this microRNA through an adeno-associated viral vector, treated animals showed marked improvements in both global and regional contractility, increased muscle mass and reduced scar size. These functional and morphological findings correlated with cardiomyocyte de-differentiation and proliferation. However, subsequent persistent and uncontrolled expression of the microRNA resulted in sudden arrhythmic death of most of the treated pigs. Such events were concurrent with myocardial infiltration of proliferating cells displaying a poorly differentiated myoblastic phenotype. These results show that achieving cardiac repair through the stimulation of endogenous cardiomyocyte proliferation is attainable in large mammals, however dosage of this therapy needs to be tightly controlled.
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The sudden cardiac failure in the porcine model was attributed to excessive cardiomyocyte dedifferentiation and proliferation that produced islands of non-contractile tissue and fatal arrhythmias.
“This was attributed to excessive cardiomyocyte dedifferentiation and proliferation that produced islands of non-contractile tissue and fatal arrhythmias.”
From 3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels (2021) · cites this paper as [59]
In a porcine MI model, prolonged expression of Hippo inhibiting miRNA-199a through viral transfection resulted in sudden cardiac failure in 70% of treated pigs.
“However, in a more recent porcine MI model, prolonged expression of Hippo inhibiting miRNA-199a through viral transfection resulted in sudden cardiac failure in 70% of the treated pigs59.”
From 3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels (2021) · cites this paper as [59]
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- Authors
- Gabisonia, K., Prosdocimo, G., Aquaro, G. D., Carlucci, L., Zentilin, L., Secco, I., Ali, H., Braga, L., Gorgodze, N., Bernini, F., Burchielli, S., Collesi, C., Zandonà, L., Sinagra, G., Piacenti, M., Zacchigna, S., Bussani, R., Recchia, F. A., & Giacca, M.
- Affiliations
- Scuola Superiore Sant'Anna (IT)
- International Centre for Genetic Engineering and Biotechnology (IT)
- Fondazione Toscana Gabriele Monasterio (IT)
- King's College London (GB)
- University of Trieste (IT)
- Corresponding author
- Recchia, Fabio A.
- Giacca, Mauro
- ORCID
- Venue
- Nature
- Published
- 2019-05
- Volume
- 569
- Issue
- 7756
- Pages
- 418-422
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6768803
- OpenAlex
- W2943870140
- Cited by
- 478
- References
- 46
- Citations by year
- 2026: 31 · 2025: 55 · 2024: 56 · 2023: 77 · 2022: 82 · 2021: 84 · 2020: 71 · 2019: 22
- FWCI
- 21.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- CINECA IRIS Institutional Research Information System (Sant'Anna School of Advanced Studies) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- miRNA-based therapy, myocardial infarction, cardiac repair, cardiomyocyte proliferation, cardiomyocyte dedifferentiation, adeno-associated virus vectors, sudden arrhythmic death, scar size, regional contractility, porcine model, heart failure
- MeSH terms
- Animals, Heart, Male, Myocardial Infarction, Regeneration, Death, Sudden, Cardiac, Myocytes, Cardiac, Sus scrofa, MicroRNAs, Cell Proliferation
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