title: Spatially Resolved Genome-wide Transcriptional Profiling Identifies BMP Signaling as Essential Regulator of Zebrafish Cardiomyocyte Regeneration.
abstract: In contrast to mammals, zebrafish regenerate heart injuries via proliferation of cardiomyocytes located near the wound border. To identify regulators of cardiomyocyte proliferation, we used spatially resolved RNA sequencing (tomo-seq) and generated a high-resolution genome-wide atlas of gene expression in the regenerating zebrafish heart. Interestingly, we identified two wound border zones with distinct expression profiles, including the re-expression of embryonic cardiac genes and targets of bone morphogenetic protein (BMP) signaling. Endogenous BMP signaling has been reported to be detrimental to mammalian cardiac repair. In contrast, we find that genetic or chemical inhibition of BMP signaling in zebrafish reduces cardiomyocyte dedifferentiation and proliferation, ultimately compromising myocardial regeneration, while bmp2b overexpression is sufficient to enhance it. Our results provide a resource for further studies on the molecular regulation of cardiac regeneration and reveal intriguing differential cellular responses of cardiomyocytes to a conserved signaling pathway in regenerative versus non-regenerative hearts.
authors.affiliation: Institute for Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Hubrecht Institute, University Medical Centre Utrecht, Uppsalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Fabian
authors.initials: F
authors.lastname: Kruse
authors.affiliation: Institute for Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Mohankrishna Dalvoy
authors.initials: MD
authors.lastname: Vasudevarao
authors.affiliation: Hubrecht Institute, University Medical Centre Utrecht, Uppsalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Jan Philipp
authors.initials: JP
authors.lastname: Junker
authors.affiliation: Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Krankenhausstr 8-10, 91054 Erlangen, Germany.
authors.forename: David C
authors.initials: DC
authors.lastname: Zebrowski
authors.affiliation: Institute of Clinical Genetics, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Hubrecht Institute, University Medical Centre Utrecht, Uppsalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Noël
authors.affiliation: Hubrecht Institute, University Medical Centre Utrecht, Uppsalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Dominic
authors.initials: D
authors.lastname: Grün
authors.affiliation: European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands; Skolkovo Institute of Science and Technology (Skoltech), Novaya Street 100, Skolkovo, Moscow Region 143025, Russia.
authors.forename: Eugene
authors.initials: E
authors.lastname: Berezikov
authors.affiliation: Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Krankenhausstr 8-10, 91054 Erlangen, Germany.
authors.forename: Felix B
authors.initials: FB
authors.lastname: Engel
authors.affiliation: Hubrecht Institute, University Medical Centre Utrecht, Uppsalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: van Oudenaarden
authors.affiliation: Institute for Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany. Electronic address: gilbert.weidinger@uni-ulm.de.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Weidinger
authors.affiliation: Hubrecht Institute, University Medical Centre Utrecht, Uppsalaan 8, 3584 CT Utrecht, the Netherlands; Medical Physiology, University Medical Centre Utrecht, Yalelaan 50, 3584 CM Utrecht, the Netherlands. Electronic address: j.bakkers@hubrecht.eu.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Bakkers
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D016678:Genome / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D029961:Zebrafish Proteins