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Interspecies comparison reveals Hmga1 as driver of cardiac regeneration [bulk RNAseq Hmga1a OE]

ABSTRACT: The prospect of repairing the heart after a myocardial infarction by promoting cardiomyocyte proliferation has gained momentum from studies showing the heart's regenerative ability in fish, amphibians and neonatal mammals. Despite evidence of varying cardiomyocyte proliferation rates among species, the molecular mechanisms driving cardiomyocyte cell cycle re-entry remain insufficiently understood. In this study, we employed spatial transcriptomics and identified high-mobility group AT-hook 1a (Hmga1a) as being upregulated in cardiomyocytes of the injury border zone in zebrafish, but not in mice. Through knock-out and cardiomyocyte-specific overexpression of hmga1a, we found that Hmga1a was required for zebrafish heart regeneration and sufficient to drive cardiomyocyte proliferation. In addition, a single injection of Hmga1 virus in injured mouse hearts resulted in increased border zone cardiomyocyte proliferation and improved heart function. Mechanistically, Hmga1 expression reduced repressive H3K27me3 histone modifications from developmentally-regulated genes and induced a border zone-like transcriptional program in adult cardiomyocytes. Our study demonstrates the value of interspecies comparisons by identifying Hmga1 as a critical driver of heart regeneration and highlights Hmga1 as a promising therapeutic candidate to improve cardiac repair after injury.

ORGANISM(S): Danio rerio

PROVIDER: GSE241157 | GEO | 2024/11/15

REPOSITORIES: GEO

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Interspecies comparison reveals Hmga1 as driver of cardiac regeneration [bulk sortChIC Hmga1a OE]

Project description:The prospect of repairing the heart after a myocardial infarction by promoting cardiomyocyte proliferation has gained momentum from studies showing the heart's regenerative ability in fish, amphibians and neonatal mammals. Despite evidence of varying cardiomyocyte proliferation rates among species, the molecular mechanisms driving cardiomyocyte cell cycle re-entry remain insufficiently understood. In this study, we employed spatial transcriptomics and identified high-mobility group AT-hook 1a (Hmga1a) as being upregulated in cardiomyocytes of the injury border zone in zebrafish, but not in mice. Through knock-out and cardiomyocyte-specific overexpression of hmga1a, we found that Hmga1a was required for zebrafish heart regeneration and sufficient to drive cardiomyocyte proliferation. In addition, a single injection of Hmga1 virus in injured mouse hearts resulted in increased border zone cardiomyocyte proliferation and improved heart function. Mechanistically, Hmga1 expression reduced repressive H3K27me3 histone modifications from developmentally-regulated genes and induced a border zone-like transcriptional program in adult cardiomyocytes. Our study demonstrates the value of interspecies comparisons by identifying Hmga1 as a critical driver of heart regeneration and highlights Hmga1 as a promising therapeutic candidate to improve cardiac repair after injury.

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Project description:While the heart regenerates poorly in mammals, efficient heart regeneration occurs in certain amphibian and fish species. Zebrafish has been used extensively to study heart regeneration, resulting in a model in which preexisting cardiomyocytes dedifferentiate and reinitiate proliferation to replace the lost myocardium. However, there is limited knowledge about the cellular processes that occur in this rare population of proliferating cardiomyocytes during heart regeneration. To identify such processes, we generated a transgenic line based on nppa expression that marks proliferating cardiomyocytes located at the wound border zone. Next we have used a single-cell RNA-sequencing approach in the regenerating adult zebrafish heart and we uncovered that proliferating border zone cardiomyocytes have very distinct transcriptomes compared to the non-proliferating remote cardiomyocytes and that they resemble embryonic cardiomyocytes. Moreover, these cells have reduced expression of mitochondrial genes and reduced mitochondrial oxidative phosphorylation activity, while glycolysis gene expression and glucose uptake are increased, indicative for metabolic reprogramming. Mechanistically, this metabolic reprogramming is induced by Nrg1/Erbb2 signaling and this mechanism is conserved in murine hearts. Furthermore, pharmacological inhibition of glycolysis impairs cardiomyocyte proliferation of both zebrafish and murine cardiomyocytes. Together these results reveal a conserved mechanism in which cardiomyocytes undergo metabolic reprogramming, which is essential for cardiomyocyte proliferation and heart regeneration and could ultimately help to develop novel methods to promote mammalian heart repair.

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Genomeâ??wide transcriptional profiling with spatial resolution identifies Bone Morphogenetic Protein signaling as essential regulator of zebrafish cardiomyocyte regeneration.

Project description:In contrast to mammals, zebrafish regenerate heart injuries via proliferation of cardiomyocytes located at the wound border. Here, we show that tomo-seq can be used to identify whole-genome transcriptional profiles of the injury zone, the border zone and the healthy myocardium. Interestingly, the border zone is characterized by the re-expression of embryonic cardiac genes that are also activated after myocardial infarction in mouse and human, including 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. To generate spatially-resolved RNA-seq data for injured zebrafish hearts (3 and 7 days-post-injury), we cryosectioned samples, extracted RNA from the individual sections, and amplified and barcoded mRNA using the CEL-seq protocol (Hashimshony et al., Cell Reports, 2012) with a few modifications. Libraries were sequenced on Illumina NextSeq using 75bp paired end sequencing.

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Project description:Deciphering the genetic and epigenetic regulation of cardiomyocyte proliferation in organisms capable of robust cardiac renewal represents an attractive inroad towards regenerating the human heart. In the highly regenerative zebrafish heart, cardiomyocytes near the wound edge undergo dramatic changes in gene expression concomitant with sarcomere disassembly, loss of cell-cell adhesion, and detachment from the extracellular matrix (ECM), which leaves them poised to divide and give rise to new muscle cells that colonize the wound. Using integrated highthroughput transcriptional and chromatin analyses, we identified correlations between gene expression changes and activating H3K4me3 and/or repressive H3K27me3 dynamics8 in cardiomyocytes following injury. Within the category of downregulated genes that gain H3K27me3, transcripts encoding sarcomere and cytoskeletal components were significantly overrepresented. To investigate a functional requirement for H3K27me3-mediated gene silencing during zebrafish heart regeneration, we generated an inducible transgenic strain expressing a mutant version of histone 3, H3.3K27M, which allowed us to inhibit H3K27me3 catalysis in cardiomyocytes during the regenerative window. Hearts composed of H3.3K27M-expressing cardiomyocytes fail to regenerate with wound edge myocardium showing heightened expression of structural genes and prominent sarcomere structures. Although cell cycle re-entry was unperturbed, cytokinesis and wound invasion were significantly compromised. Collectively, our study identifies a requirement for H3K27me3-mediated silencing of structural genes during zebrafish heart regeneration and suggests that repression of similar structural components in the border zone of the infarcted human heart might improve its regenerative capacity.

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