A microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration

Raso A, Dirkx E, Sampaio-Pinto V, el Azzouzi H, Cubero RJ, Sorensen DW, Ottaviani L, Olieslagers S, Huibers MM, de Weger R, Siddiqi S, Moimas S, Torrini C, Zentillin L, Braga L, Nascimento DS, da Costa Martins PA, van Berlo JH, Zacchigna S, Giacca M, De Windt LJ. 2021. A microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration. Nature Communications. 12(1), 4808.

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Journal Article | Published | English
Author
Raso, Andrea; Dirkx, Ellen; Sampaio-Pinto, Vasco; el Azzouzi, Hamid; Cubero, Ryan JohnIST Austria ; Sorensen, Daniel W.; Ottaviani, Lara; Olieslagers, Servé; Huibers, Manon M.; de Weger, Roel; Siddiqi, Sailay; Moimas, Silvia
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Department
Abstract
Myocardial regeneration is restricted to early postnatal life, when mammalian cardiomyocytes still retain the ability to proliferate. The molecular cues that induce cell cycle arrest of neonatal cardiomyocytes towards terminally differentiated adult heart muscle cells remain obscure. Here we report that the miR-106b~25 cluster is higher expressed in the early postnatal myocardium and decreases in expression towards adulthood, especially under conditions of overload, and orchestrates the transition of cardiomyocyte hyperplasia towards cell cycle arrest and hypertrophy by virtue of its targetome. In line, gene delivery of miR-106b~25 to the mouse heart provokes cardiomyocyte proliferation by targeting a network of negative cell cycle regulators including E2f5, Cdkn1c, Ccne1 and Wee1. Conversely, gene-targeted miR-106b~25 null mice display spontaneous hypertrophic remodeling and exaggerated remodeling to overload by derepression of the prohypertrophic transcription factors Hand2 and Mef2d. Taking advantage of the regulatory function of miR-106b~25 on cardiomyocyte hyperplasia and hypertrophy, viral gene delivery of miR-106b~25 provokes nearly complete regeneration of the adult myocardium after ischemic injury. Our data demonstrate that exploitation of conserved molecular programs can enhance the regenerative capacity of the injured heart.
Publishing Year
Date Published
2021-08-10
Journal Title
Nature Communications
Acknowledgement
E.D. is supported by a VENI award 916-150-16 from the Netherlands Organization for Health Research and Development (ZonMW), an EMBO Long-term Fellowship (EMBO ALTF 848-2013) and a FP7 Marie Curie Intra-European Fellowship (Project number 627539). V.S.P. was funded by a fellowship from the FCT/ Ministério da Ciência, Tecnologia e Inovação SFRH/BD/111799/2015. P.D.C.M. is an Established Investigator of the Dutch Heart Foundation. L.D.W. acknowledges support from the Dutch CardioVascular Alliance (ARENA-PRIME). L.D.W. was further supported by grant 311549 from the European Research Council (ERC), a VICI award 918-156-47 from the Dutch Research Council and Marie Sklodowska-Curie grant agreement no. 813716 (TRAIN-HEART).
Volume
12
Issue
1
Article Number
4808
eISSN
IST-REx-ID

Cite this

Raso A, Dirkx E, Sampaio-Pinto V, et al. A microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration. Nature Communications. 2021;12(1). doi:10.1038/s41467-021-25211-4
Raso, A., Dirkx, E., Sampaio-Pinto, V., el Azzouzi, H., Cubero, R. J., Sorensen, D. W., … De Windt, L. J. (2021). A microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration. Nature Communications. Springer Nature. https://doi.org/10.1038/s41467-021-25211-4
Raso, Andrea, Ellen Dirkx, Vasco Sampaio-Pinto, Hamid el Azzouzi, Ryan J Cubero, Daniel W. Sorensen, Lara Ottaviani, et al. “A MicroRNA Program Regulates the Balance between Cardiomyocyte Hyperplasia and Hypertrophy and Stimulates Cardiac Regeneration.” Nature Communications. Springer Nature, 2021. https://doi.org/10.1038/s41467-021-25211-4.
A. Raso et al., “A microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration,” Nature Communications, vol. 12, no. 1. Springer Nature, 2021.
Raso A, Dirkx E, Sampaio-Pinto V, el Azzouzi H, Cubero RJ, Sorensen DW, Ottaviani L, Olieslagers S, Huibers MM, de Weger R, Siddiqi S, Moimas S, Torrini C, Zentillin L, Braga L, Nascimento DS, da Costa Martins PA, van Berlo JH, Zacchigna S, Giacca M, De Windt LJ. 2021. A microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration. Nature Communications. 12(1), 4808.
Raso, Andrea, et al. “A MicroRNA Program Regulates the Balance between Cardiomyocyte Hyperplasia and Hypertrophy and Stimulates Cardiac Regeneration.” Nature Communications, vol. 12, no. 1, 4808, Springer Nature, 2021, doi:10.1038/s41467-021-25211-4.
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