Spatially Resolved Genome-wide Transcriptional Profiling Identifies BMP Signaling as Essential Regulator of Zebrafish Cardiomyocyte Regeneration

TY - JOUR

T1 - Spatially Resolved Genome-wide Transcriptional Profiling Identifies BMP Signaling as Essential Regulator of Zebrafish Cardiomyocyte Regeneration

AU - Wu, Chi-Chung

AU - Kruse, Fabian

AU - Vasudevarao, Mohankrishna Dalvoy

AU - Junker, Jan Philipp

AU - Zebrowski, David C

AU - Fischer, Kristin

AU - Noël, Emily S

AU - Grün, Dominic

AU - Berezikov, Eugene

AU - Engel, Felix B

AU - van Oudenaarden, Alexander

AU - Weidinger, Gilbert

AU - Bakkers, Jeroen

N1 - Copyright © 2016 Elsevier Inc. All rights reserved.

PY - 2016/1/11

Y1 - 2016/1/11

N2 - 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.

AB - 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.

KW - Animals

KW - Bone Morphogenetic Proteins

KW - Cell Differentiation

KW - Cell Proliferation

KW - Gene Expression Regulation

KW - Genome

KW - Myocytes, Cardiac

KW - Regeneration

KW - Signal Transduction

KW - Zebrafish

KW - Zebrafish Proteins

U2 - 10.1016/j.devcel.2015.12.010

DO - 10.1016/j.devcel.2015.12.010

M3 - Article

C2 - 26748692

SN - 1534-5807

VL - 36

SP - 36

EP - 49

JO - Developmental Cell

JF - Developmental Cell

IS - 1

ER -