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

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. [Display omitted] •Tomo-seq reveals spatial gene expression profiles of regenerating zebrafish hearts•The wound border zone expresses regulators and targets of BMP signaling•BMP signaling is activated in cardiomyocytes and promotes their proliferation•Heart regeneration requires BMP signaling and is enhanced by pathway activation Wu, Kruse et al. apply tomo-seq, a technique for spatially resolved genome-wide transcriptional profiling, to the regenerating zebrafish heart. They identify BMP signaling as an essential regulator of zebrafish cardiomyocyte regeneration, via regulating injury-induced cardiomyocyte dedifferentiation and proliferation.