BMP7 promotes cardiomyocyte regeneration in zebrafish and adult mice

Chiara Bongiovanni; Hanna Bueno-Levy; Denise Posadas Pena; Irene Del Bono; Carmen Miano; Stefano Boriati; Silvia Da Pra; Francesca Sacchi; Simone Redaelli; Max Bergen; Donatella Romaniello; Francesca Pontis; Riccardo Tassinari; Laura Kellerer; Ilaria Petraroia; Martina Mazzeschi; Mattia Lauriola; Carlo Ventura; Stephan Heermann; Gilbert Weidinger; Eldad Tzahor; Gabriele D'Uva

doi:10.1016/j.celrep.2024.114162

BMP7 promotes cardiomyocyte regeneration in zebrafish and adult mice

Chiara Bongiovanni, Hanna Bueno-Levy, Denise Posadas Pena, Irene Del Bono, Carmen Miano, Stefano Boriati, Silvia Da Pra, Francesca Sacchi, Simone Redaelli, Max Bergen, Donatella Romaniello, Francesca Pontis, Riccardo Tassinari, Laura Kellerer, Ilaria Petraroia, Martina Mazzeschi, Mattia Lauriola, Carlo Ventura, Stephan Heermann, Gilbert WeidingerEldad Tzahor, Gabriele D'Uva^*

^*Corresponding author for this work

Department of Molecular Cell Biology

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

1 Citation (Scopus)

Abstract

Zebrafish have a lifelong cardiac regenerative ability after damage, whereas mammals lose this capacity during early postnatal development. This study investigated whether the declining expression of growth factors during postnatal mammalian development contributes to the decrease of cardiomyocyte regenerative potential. Besides confirming the proliferative ability of neuregulin 1 (NRG1), interleukin (IL)1b, receptor activator of nuclear factor kappa-Β ligand (RANKL), insulin growth factor (IGF)2, and IL6, we identified other potential pro-regenerative factors, with BMP7 exhibiting the most pronounced efficacy. Bmp7 knockdown in neonatal mouse cardiomyocytes and loss-of-function in adult zebrafish during cardiac regeneration reduced cardiomyocyte proliferation, indicating that Bmp7 is crucial in the regenerative stages of mouse and zebrafish hearts. Conversely, bmp7 overexpression in regenerating zebrafish or administration at post-mitotic juvenile and adult mouse stages, in vitro and in vivo following myocardial infarction, enhanced cardiomyocyte cycling. Mechanistically, BMP7 stimulated proliferation through BMPR1A/ACVR1 and ACVR2A/BMPR2 receptors and downstream SMAD5, ERK, and AKT signaling. Overall, BMP7 administration is a promising strategy for heart regeneration.

Original language	English
Article number	114162
Journal	Cell Reports
Volume	43
Issue number	5
Early online date	27 Apr 2024
DOIs	https://doi.org/10.1016/j.celrep.2024.114162
Publication status	Published - 28 May 2024

Bibliographical note

The research leading to these results has received funding from the European Union - NextGenerationEU through the Italian Ministry of University and Research under PNRR - M4C2-I1.3 Project PE_00000019 “HEAL ITALIA” to G.D'U. CUP J33C22002920006. The views and opinions expressed are those of the authors only and do not necessarily reflect those of the European Union or the European Commission. Neither the European Union nor the European Commission can be responsible for them. The research was also supported by the European Union’s Horizon 2020 research and innovation programme under the ERA-NET on Cardiovascular Diseases (ERA-CVD) Co-fund action to G.D'U., G.W., and E.T. (Grant Number: JCT2016-40-080), by Fondazione Luisa Fanti Melloni to G.D'U., and by the Italian Ministry of Health (RC-2024-2790614). The D’Uva lab extends its gratitude to Milena Pariali for her technical support in sectioning paraffin-embedded samples and to Desirè Zambroni for her technical assistance in in vitro immunofluorescence imaging at ALEMBIC, an advanced microscopy laboratory established by IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele.

E.T. was supported by the European Research Council (ERC AdG #788194), the European Union’s Horizon 2020 research and innovation programme (874764), and the Israel Science Foundation (ISF).

G.W. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Project-ID 251293561 – SFB 1149 (project C03), project ID 316249678 – SFB 1279 (project Z02), and project ID 450627322 – SFB 1506 (project C04). The Weidinger lab acknowledges the Core facility “light microscopy” of the Medical Faculty of Ulm University for help with imaging.

Publisher Copyright:
© 2024 The Author(s)

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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Bongiovanni, C., Bueno-Levy, H., Posadas Pena, D., Del Bono, I., Miano, C., Boriati, S., Da Pra, S., Sacchi, F., Redaelli, S., Bergen, M., Romaniello, D., Pontis, F., Tassinari, R., Kellerer, L., Petraroia, I., Mazzeschi, M., Lauriola, M., Ventura, C., Heermann, S., ... D'Uva, G. (2024). BMP7 promotes cardiomyocyte regeneration in zebrafish and adult mice. Cell Reports, 43(5), Article 114162. https://doi.org/10.1016/j.celrep.2024.114162

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title = "BMP7 promotes cardiomyocyte regeneration in zebrafish and adult mice",

abstract = "Zebrafish have a lifelong cardiac regenerative ability after damage, whereas mammals lose this capacity during early postnatal development. This study investigated whether the declining expression of growth factors during postnatal mammalian development contributes to the decrease of cardiomyocyte regenerative potential. Besides confirming the proliferative ability of neuregulin 1 (NRG1), interleukin (IL)1b, receptor activator of nuclear factor kappa-Β ligand (RANKL), insulin growth factor (IGF)2, and IL6, we identified other potential pro-regenerative factors, with BMP7 exhibiting the most pronounced efficacy. Bmp7 knockdown in neonatal mouse cardiomyocytes and loss-of-function in adult zebrafish during cardiac regeneration reduced cardiomyocyte proliferation, indicating that Bmp7 is crucial in the regenerative stages of mouse and zebrafish hearts. Conversely, bmp7 overexpression in regenerating zebrafish or administration at post-mitotic juvenile and adult mouse stages, in vitro and in vivo following myocardial infarction, enhanced cardiomyocyte cycling. Mechanistically, BMP7 stimulated proliferation through BMPR1A/ACVR1 and ACVR2A/BMPR2 receptors and downstream SMAD5, ERK, and AKT signaling. Overall, BMP7 administration is a promising strategy for heart regeneration.",

author = "Chiara Bongiovanni and Hanna Bueno-Levy and {Posadas Pena}, Denise and {Del Bono}, Irene and Carmen Miano and Stefano Boriati and {Da Pra}, Silvia and Francesca Sacchi and Simone Redaelli and Max Bergen and Donatella Romaniello and Francesca Pontis and Riccardo Tassinari and Laura Kellerer and Ilaria Petraroia and Martina Mazzeschi and Mattia Lauriola and Carlo Ventura and Stephan Heermann and Gilbert Weidinger and Eldad Tzahor and Gabriele D'Uva",

note = "The research leading to these results has received funding from the European Union - NextGenerationEU through the Italian Ministry of University and Research under PNRR - M4C2-I1.3 Project PE_00000019 “HEAL ITALIA” to G.D'U. CUP J33C22002920006. The views and opinions expressed are those of the authors only and do not necessarily reflect those of the European Union or the European Commission. Neither the European Union nor the European Commission can be responsible for them. The research was also supported by the European Union{\textquoteright}s Horizon 2020 research and innovation programme under the ERA-NET on Cardiovascular Diseases (ERA-CVD) Co-fund action to G.D'U., G.W., and E.T. (Grant Number: JCT2016-40-080), by Fondazione Luisa Fanti Melloni to G.D'U., and by the Italian Ministry of Health (RC-2024-2790614). The D{\textquoteright}Uva lab extends its gratitude to Milena Pariali for her technical support in sectioning paraffin-embedded samples and to Desir{\`e} Zambroni for her technical assistance in in vitro immunofluorescence imaging at ALEMBIC, an advanced microscopy laboratory established by IRCCS Ospedale San Raffaele and Universit{\`a} Vita-Salute San Raffaele. E.T. was supported by the European Research Council (ERC AdG #788194), the European Union{\textquoteright}s Horizon 2020 research and innovation programme (874764), and the Israel Science Foundation (ISF). G.W. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Project-ID 251293561 – SFB 1149 (project C03), project ID 316249678 – SFB 1279 (project Z02), and project ID 450627322 – SFB 1506 (project C04). The Weidinger lab acknowledges the Core facility “light microscopy” of the Medical Faculty of Ulm University for help with imaging. Publisher Copyright: {\textcopyright} 2024 The Author(s)",

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doi = "10.1016/j.celrep.2024.114162",

language = "English",

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Bongiovanni, C, Bueno-Levy, H, Posadas Pena, D, Del Bono, I, Miano, C, Boriati, S, Da Pra, S, Sacchi, F, Redaelli, S, Bergen, M, Romaniello, D, Pontis, F, Tassinari, R, Kellerer, L, Petraroia, I, Mazzeschi, M, Lauriola, M, Ventura, C, Heermann, S, Weidinger, G, Tzahor, E & D'Uva, G 2024, 'BMP7 promotes cardiomyocyte regeneration in zebrafish and adult mice', Cell Reports, vol. 43, no. 5, 114162. https://doi.org/10.1016/j.celrep.2024.114162

TY - JOUR

T1 - BMP7 promotes cardiomyocyte regeneration in zebrafish and adult mice

AU - Bongiovanni, Chiara

AU - Bueno-Levy, Hanna

AU - Posadas Pena, Denise

AU - Del Bono, Irene

AU - Miano, Carmen

AU - Boriati, Stefano

AU - Da Pra, Silvia

AU - Sacchi, Francesca

AU - Redaelli, Simone

AU - Bergen, Max

AU - Romaniello, Donatella

AU - Pontis, Francesca

AU - Tassinari, Riccardo

AU - Kellerer, Laura

AU - Petraroia, Ilaria

AU - Mazzeschi, Martina

AU - Lauriola, Mattia

AU - Ventura, Carlo

AU - Heermann, Stephan

AU - Weidinger, Gilbert

AU - Tzahor, Eldad

AU - D'Uva, Gabriele

N1 - The research leading to these results has received funding from the European Union - NextGenerationEU through the Italian Ministry of University and Research under PNRR - M4C2-I1.3 Project PE_00000019 “HEAL ITALIA” to G.D'U. CUP J33C22002920006. The views and opinions expressed are those of the authors only and do not necessarily reflect those of the European Union or the European Commission. Neither the European Union nor the European Commission can be responsible for them. The research was also supported by the European Union’s Horizon 2020 research and innovation programme under the ERA-NET on Cardiovascular Diseases (ERA-CVD) Co-fund action to G.D'U., G.W., and E.T. (Grant Number: JCT2016-40-080), by Fondazione Luisa Fanti Melloni to G.D'U., and by the Italian Ministry of Health (RC-2024-2790614). The D’Uva lab extends its gratitude to Milena Pariali for her technical support in sectioning paraffin-embedded samples and to Desirè Zambroni for her technical assistance in in vitro immunofluorescence imaging at ALEMBIC, an advanced microscopy laboratory established by IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele. E.T. was supported by the European Research Council (ERC AdG #788194), the European Union’s Horizon 2020 research and innovation programme (874764), and the Israel Science Foundation (ISF). G.W. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Project-ID 251293561 – SFB 1149 (project C03), project ID 316249678 – SFB 1279 (project Z02), and project ID 450627322 – SFB 1506 (project C04). The Weidinger lab acknowledges the Core facility “light microscopy” of the Medical Faculty of Ulm University for help with imaging. Publisher Copyright: © 2024 The Author(s)

PY - 2024/5/28

Y1 - 2024/5/28

N2 - Zebrafish have a lifelong cardiac regenerative ability after damage, whereas mammals lose this capacity during early postnatal development. This study investigated whether the declining expression of growth factors during postnatal mammalian development contributes to the decrease of cardiomyocyte regenerative potential. Besides confirming the proliferative ability of neuregulin 1 (NRG1), interleukin (IL)1b, receptor activator of nuclear factor kappa-Β ligand (RANKL), insulin growth factor (IGF)2, and IL6, we identified other potential pro-regenerative factors, with BMP7 exhibiting the most pronounced efficacy. Bmp7 knockdown in neonatal mouse cardiomyocytes and loss-of-function in adult zebrafish during cardiac regeneration reduced cardiomyocyte proliferation, indicating that Bmp7 is crucial in the regenerative stages of mouse and zebrafish hearts. Conversely, bmp7 overexpression in regenerating zebrafish or administration at post-mitotic juvenile and adult mouse stages, in vitro and in vivo following myocardial infarction, enhanced cardiomyocyte cycling. Mechanistically, BMP7 stimulated proliferation through BMPR1A/ACVR1 and ACVR2A/BMPR2 receptors and downstream SMAD5, ERK, and AKT signaling. Overall, BMP7 administration is a promising strategy for heart regeneration.

AB - Zebrafish have a lifelong cardiac regenerative ability after damage, whereas mammals lose this capacity during early postnatal development. This study investigated whether the declining expression of growth factors during postnatal mammalian development contributes to the decrease of cardiomyocyte regenerative potential. Besides confirming the proliferative ability of neuregulin 1 (NRG1), interleukin (IL)1b, receptor activator of nuclear factor kappa-Β ligand (RANKL), insulin growth factor (IGF)2, and IL6, we identified other potential pro-regenerative factors, with BMP7 exhibiting the most pronounced efficacy. Bmp7 knockdown in neonatal mouse cardiomyocytes and loss-of-function in adult zebrafish during cardiac regeneration reduced cardiomyocyte proliferation, indicating that Bmp7 is crucial in the regenerative stages of mouse and zebrafish hearts. Conversely, bmp7 overexpression in regenerating zebrafish or administration at post-mitotic juvenile and adult mouse stages, in vitro and in vivo following myocardial infarction, enhanced cardiomyocyte cycling. Mechanistically, BMP7 stimulated proliferation through BMPR1A/ACVR1 and ACVR2A/BMPR2 receptors and downstream SMAD5, ERK, and AKT signaling. Overall, BMP7 administration is a promising strategy for heart regeneration.

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SN - 2211-1247

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JO - Cell Reports

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BMP7 promotes cardiomyocyte regeneration in zebrafish and adult mice

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