In vivo activation of a conserved microRNA program induces mammalian heart regeneration

Aitor Aguirre; Nuria Montserrat; Serena Zacchigna; Emmanuel Nivet; Tomoaki Hishida; Marie N. Krause; Leo Kurian; Alejandro Ocampo; Eric Vazquez-Ferrer; Concepcion Rodriguez-Esteban; Sachin Kumar; James J. Moresco; John R. Yates; Josep M. Campistol; Ignacio Sancho-Martinez; Mauro Giacca; Juan Carlos Izpisua Belmonte

doi:10.1016/j.stem.2014.10.003

In vivo activation of a conserved microRNA program induces mammalian heart regeneration

Aitor Aguirre, Nuria Montserrat, Serena Zacchigna, Emmanuel Nivet, Tomoaki Hishida, Marie N. Krause, Leo Kurian, Alejandro Ocampo, Eric Vazquez-Ferrer, Concepcion Rodriguez-Esteban, Sachin Kumar, James J. Moresco, John R. Yates, Josep M. Campistol, Ignacio Sancho-Martinez, Mauro Giacca, Juan Carlos Izpisua Belmonte^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

157 Scopus citations

Abstract

Heart failure is a leading cause of mortality and morbidity in the developed world, partly because mammals lack the ability to regenerate heart tissue. Whether this is due to evolutionary loss of regenerative mechanisms present in other organisms or to an inability to activate such mechanisms is currently unclear. Here we decipher mechanisms underlying heart regeneration in adult zebrafish and show that the molecular regulators of this response are conserved in mammals. We identified miR-99/100 and Let-7a/c and their protein targets smarca5 and fntb as critical regulators of cardiomyocyte dedifferentiation and heart regeneration in zebrafish. Although human and murine adult cardiomyocytes fail to elicit an endogenous regenerative response after myocardial infarction, we show that in vivo manipulation of this molecular machinery in mice results in cardiomyocyte dedifferentiation and improved heart functionality after injury. These data provide a proof of concept for identifying and activating conserved molecular programs to regenerate the damaged heart.

Original language	English (US)
Pages (from-to)	589-604
Number of pages	16
Journal	Cell Stem Cell
Volume	15
Issue number	5
DOIs	https://doi.org/10.1016/j.stem.2014.10.003
State	Published - 2014
Externally published	Yes

Bibliographical note

Funding Information:
We thank M. Schwarz and P. Schwarz for administrative support. We are grateful to Thai B. Nguyen, Yun Xia, Chris Benner, Daiji Okamura, Manching Ku, James Kasubowski, Merce Marti, and the Waitt Advanced Biophotonicis Core at the Salk Institute for excellent technical assistance and useful discussions. We would also like to thank Louise C. Laurent and Robert Morey for their help with bioinformatics analyses. A.A. was partially supported by the Ipsen Foundation. L.K. was partially supported by a training grant from the California Institute for Regenerative Medicine. I.S.M. was partially supported by a Nomis Foundation postdoctoral fellowship. Work in the lab of J.Y. was supported by National Institute of General Medical Sciences (8 P41 GM103533) and UCLA/NHLBI Proteomics Centers (HHSN268201000035C). Work in the laboratory of J.C.I.B. was supported by grants from MINECO PLE2009-0100 (CMRB), the NHLBI (U01 HL107442-04), the G. Harold and Leila Y. Mathers Charitable Foundation, and The Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002) (Salk Institute).

Publisher Copyright:
©2014 Elsevier Inc.

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.stem.2014.10.003

Cite this

Aguirre, A., Montserrat, N., Zacchigna, S., Nivet, E., Hishida, T., Krause, M. N., Kurian, L., Ocampo, A., Vazquez-Ferrer, E., Rodriguez-Esteban, C., Kumar, S., Moresco, J. J., Yates, J. R., Campistol, J. M., Sancho-Martinez, I., Giacca, M., & Izpisua Belmonte, J. C. (2014). In vivo activation of a conserved microRNA program induces mammalian heart regeneration. Cell Stem Cell, 15(5), 589-604. https://doi.org/10.1016/j.stem.2014.10.003

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title = "In vivo activation of a conserved microRNA program induces mammalian heart regeneration",

abstract = "Heart failure is a leading cause of mortality and morbidity in the developed world, partly because mammals lack the ability to regenerate heart tissue. Whether this is due to evolutionary loss of regenerative mechanisms present in other organisms or to an inability to activate such mechanisms is currently unclear. Here we decipher mechanisms underlying heart regeneration in adult zebrafish and show that the molecular regulators of this response are conserved in mammals. We identified miR-99/100 and Let-7a/c and their protein targets smarca5 and fntb as critical regulators of cardiomyocyte dedifferentiation and heart regeneration in zebrafish. Although human and murine adult cardiomyocytes fail to elicit an endogenous regenerative response after myocardial infarction, we show that in vivo manipulation of this molecular machinery in mice results in cardiomyocyte dedifferentiation and improved heart functionality after injury. These data provide a proof of concept for identifying and activating conserved molecular programs to regenerate the damaged heart.",

author = "Aitor Aguirre and Nuria Montserrat and Serena Zacchigna and Emmanuel Nivet and Tomoaki Hishida and Krause, {Marie N.} and Leo Kurian and Alejandro Ocampo and Eric Vazquez-Ferrer and Concepcion Rodriguez-Esteban and Sachin Kumar and Moresco, {James J.} and Yates, {John R.} and Campistol, {Josep M.} and Ignacio Sancho-Martinez and Mauro Giacca and {Izpisua Belmonte}, {Juan Carlos}",

note = "Funding Information: We thank M. Schwarz and P. Schwarz for administrative support. We are grateful to Thai B. Nguyen, Yun Xia, Chris Benner, Daiji Okamura, Manching Ku, James Kasubowski, Merce Marti, and the Waitt Advanced Biophotonicis Core at the Salk Institute for excellent technical assistance and useful discussions. We would also like to thank Louise C. Laurent and Robert Morey for their help with bioinformatics analyses. A.A. was partially supported by the Ipsen Foundation. L.K. was partially supported by a training grant from the California Institute for Regenerative Medicine. I.S.M. was partially supported by a Nomis Foundation postdoctoral fellowship. Work in the lab of J.Y. was supported by National Institute of General Medical Sciences (8 P41 GM103533) and UCLA/NHLBI Proteomics Centers (HHSN268201000035C). Work in the laboratory of J.C.I.B. was supported by grants from MINECO PLE2009-0100 (CMRB), the NHLBI (U01 HL107442-04), the G. Harold and Leila Y. Mathers Charitable Foundation, and The Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002) (Salk Institute). Publisher Copyright: {\textcopyright}2014 Elsevier Inc.",

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Aguirre, A, Montserrat, N, Zacchigna, S, Nivet, E, Hishida, T, Krause, MN, Kurian, L, Ocampo, A, Vazquez-Ferrer, E, Rodriguez-Esteban, C, Kumar, S, Moresco, JJ, Yates, JR, Campistol, JM, Sancho-Martinez, I, Giacca, M & Izpisua Belmonte, JC 2014, 'In vivo activation of a conserved microRNA program induces mammalian heart regeneration', Cell Stem Cell, vol. 15, no. 5, pp. 589-604. https://doi.org/10.1016/j.stem.2014.10.003

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T1 - In vivo activation of a conserved microRNA program induces mammalian heart regeneration

AU - Aguirre, Aitor

AU - Montserrat, Nuria

AU - Zacchigna, Serena

AU - Nivet, Emmanuel

AU - Hishida, Tomoaki

AU - Krause, Marie N.

AU - Kurian, Leo

AU - Ocampo, Alejandro

AU - Vazquez-Ferrer, Eric

AU - Rodriguez-Esteban, Concepcion

AU - Kumar, Sachin

AU - Moresco, James J.

AU - Yates, John R.

AU - Campistol, Josep M.

AU - Sancho-Martinez, Ignacio

AU - Giacca, Mauro

AU - Izpisua Belmonte, Juan Carlos

N1 - Funding Information: We thank M. Schwarz and P. Schwarz for administrative support. We are grateful to Thai B. Nguyen, Yun Xia, Chris Benner, Daiji Okamura, Manching Ku, James Kasubowski, Merce Marti, and the Waitt Advanced Biophotonicis Core at the Salk Institute for excellent technical assistance and useful discussions. We would also like to thank Louise C. Laurent and Robert Morey for their help with bioinformatics analyses. A.A. was partially supported by the Ipsen Foundation. L.K. was partially supported by a training grant from the California Institute for Regenerative Medicine. I.S.M. was partially supported by a Nomis Foundation postdoctoral fellowship. Work in the lab of J.Y. was supported by National Institute of General Medical Sciences (8 P41 GM103533) and UCLA/NHLBI Proteomics Centers (HHSN268201000035C). Work in the laboratory of J.C.I.B. was supported by grants from MINECO PLE2009-0100 (CMRB), the NHLBI (U01 HL107442-04), the G. Harold and Leila Y. Mathers Charitable Foundation, and The Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002) (Salk Institute). Publisher Copyright: ©2014 Elsevier Inc.

PY - 2014

Y1 - 2014

N2 - Heart failure is a leading cause of mortality and morbidity in the developed world, partly because mammals lack the ability to regenerate heart tissue. Whether this is due to evolutionary loss of regenerative mechanisms present in other organisms or to an inability to activate such mechanisms is currently unclear. Here we decipher mechanisms underlying heart regeneration in adult zebrafish and show that the molecular regulators of this response are conserved in mammals. We identified miR-99/100 and Let-7a/c and their protein targets smarca5 and fntb as critical regulators of cardiomyocyte dedifferentiation and heart regeneration in zebrafish. Although human and murine adult cardiomyocytes fail to elicit an endogenous regenerative response after myocardial infarction, we show that in vivo manipulation of this molecular machinery in mice results in cardiomyocyte dedifferentiation and improved heart functionality after injury. These data provide a proof of concept for identifying and activating conserved molecular programs to regenerate the damaged heart.

AB - Heart failure is a leading cause of mortality and morbidity in the developed world, partly because mammals lack the ability to regenerate heart tissue. Whether this is due to evolutionary loss of regenerative mechanisms present in other organisms or to an inability to activate such mechanisms is currently unclear. Here we decipher mechanisms underlying heart regeneration in adult zebrafish and show that the molecular regulators of this response are conserved in mammals. We identified miR-99/100 and Let-7a/c and their protein targets smarca5 and fntb as critical regulators of cardiomyocyte dedifferentiation and heart regeneration in zebrafish. Although human and murine adult cardiomyocytes fail to elicit an endogenous regenerative response after myocardial infarction, we show that in vivo manipulation of this molecular machinery in mice results in cardiomyocyte dedifferentiation and improved heart functionality after injury. These data provide a proof of concept for identifying and activating conserved molecular programs to regenerate the damaged heart.

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DO - 10.1016/j.stem.2014.10.003

M3 - Article

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AN - SCOPUS:84922646378

SN - 1934-5909

VL - 15

SP - 589

EP - 604

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 5

ER -

In vivo activation of a conserved microRNA program induces mammalian heart regeneration

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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