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
Affiliations
Chiara Bongiovanni
Department of Medical and Surgical Sciences, University of Bologna, via Massarenti 9, 40138 Bologna, Italy; Centre for Applied Biomedical Research (CRBA), University of Bologna, via Massarenti 9, 40138 Bologna, Italy; National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems (INBB), via di Corticella 183, 40128 Bologna, Italy
Hanna Bueno-Levy
Department of Molecular Cell Biology, Weizmann Institute of Science, Herzl St. 234, Rehovot 76100, Israel
Denise Posadas Pena
Institute of Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany
Irene Del Bono
Department of Medical and Surgical Sciences, University of Bologna, via Massarenti 9, 40138 Bologna, Italy; Centre for Applied Biomedical Research (CRBA), University of Bologna, via Massarenti 9, 40138 Bologna, Italy
Carmen Miano
Department of Medical and Surgical Sciences, University of Bologna, via Massarenti 9, 40138 Bologna, Italy; Centre for Applied Biomedical Research (CRBA), University of Bologna, via Massarenti 9, 40138 Bologna, Italy; National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems (INBB), via di Corticella 183, 40128 Bologna, Italy
Stefano Boriati
Department of Medical and Surgical Sciences, University of Bologna, via Massarenti 9, 40138 Bologna, Italy; Centre for Applied Biomedical Research (CRBA), University of Bologna, via Massarenti 9, 40138 Bologna, Italy
Silvia Da Pra
Department of Medical and Surgical Sciences, University of Bologna, via Massarenti 9, 40138 Bologna, Italy; Centre for Applied Biomedical Research (CRBA), University of Bologna, via Massarenti 9, 40138 Bologna, Italy
Francesca Sacchi
Department of Medical and Surgical Sciences, University of Bologna, via Massarenti 9, 40138 Bologna, Italy; Centre for Applied Biomedical Research (CRBA), University of Bologna, via Massarenti 9, 40138 Bologna, Italy; National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems (INBB), via di Corticella 183, 40128 Bologna, Italy
Simone Redaelli
Institute of Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany
Max Bergen
Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Albertstrasse 17, 79104 Freiburg, Germany
Donatella Romaniello
Department of Medical and Surgical Sciences, University of Bologna, via Massarenti 9, 40138 Bologna, Italy; Centre for Applied Biomedical Research (CRBA), University of Bologna, via Massarenti 9, 40138 Bologna, Italy
Francesca Pontis
Scientific and Technological Pole, IRCCS MultiMedica, via Fantoli 16/15, 20138 Milan, Italy
Riccardo Tassinari
Eldor Lab, via di Corticella 183, 40128 Bologna, Italy
Laura Kellerer
Institute of Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany
Ilaria Petraroia
Scientific and Technological Pole, IRCCS MultiMedica, via Fantoli 16/15, 20138 Milan, Italy
Martina Mazzeschi
IRCCS Azienda Ospedaliero-Universitaria di Bologna, via Massarenti 9, 40138 Bologna, Italy
Mattia Lauriola
Department of Medical and Surgical Sciences, University of Bologna, via Massarenti 9, 40138 Bologna, Italy; Centre for Applied Biomedical Research (CRBA), University of Bologna, via Massarenti 9, 40138 Bologna, Italy
Carlo Ventura
Department of Medical and Surgical Sciences, University of Bologna, via Massarenti 9, 40138 Bologna, Italy; National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems (INBB), via di Corticella 183, 40128 Bologna, Italy
Stephan Heermann
Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Albertstrasse 17, 79104 Freiburg, Germany
Gilbert Weidinger
Institute of Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany
Eldad Tzahor
Department of Molecular Cell Biology, Weizmann Institute of Science, Herzl St. 234, Rehovot 76100, Israel
Gabriele D’Uva
Department of Medical and Surgical Sciences, University of Bologna, via Massarenti 9, 40138 Bologna, Italy; IRCCS Azienda Ospedaliero-Universitaria di Bologna, via Massarenti 9, 40138 Bologna, Italy; Corresponding author
Summary: 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.
