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Interspecies comparison reveals Hmga1 as a key determinator of cardiac regenerative potential

ABSTRACT: Myocardial infarction causes a massive loss of cardiomyocytes, leading to the formation of a fibrotic scar resulting in impaired cardiac function. In contrast to mammals, zebrafish display robust cardiac regeneration following injury due to the proliferation of pre-existing cardiomyocytes in the injury border zone. Here, we aim to identify transcriptomic differences that will help explain the differential cardiac regenerative capacity observed between the injured zebrafish and mammalian heart. First, we transcriptionally profiled the border zone of the injured mouse heart, which does not support regeneration. Then, we bioinformatically compared the transcriptome of the mouse border zone with the zebrafish border zone, identifying many genes and processes overlapping or diverging between the two species. Interestingly, we identified the architectural chromatin remodeller hmga1a to be expressed in the zebrafish, but not the mouse border zone. Using a loss-of-function hmga1a mutant we show that hmga1a is required for border zone cardiomyocyte proliferation and zebrafish heart regeneration. Using single-cell RNA-sequencing, we identify the near absence of proliferative cardiomyocyte sub-populations in hmga1a mutant border zones. Furthermore, we show that overexpression of hmga1a can induce cardiomyocyte proliferation in uninjured zebrafish hearts. Using a combination of RNA- and ATAC-sequencing, we show that hmga1a overexpression leads to the induction of a broad border zone-like gene program, including robust chromatin remodelling. Last, we provide evidence suggesting that overexpression of Hmga1 can stimulate mammalian cardiomyocyte proliferation and functional recovery post myocardial infarction. Taken together, through transcriptional comparison of the zebrafish and mouse border zone we have identified hmga1a as a key determinator of cardiac regenerative potential.

ORGANISM(S): Danio rerio

PROVIDER: GSE164729 | GEO | 2025/01/01

REPOSITORIES: GEO

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Project description:Ischemic cardiopathy is the leading cause of death in the world, for which efficient regenerative therapy is not currently available. In mammals, after a myocardial infarction episode, the damaged myocardium is replaced by scar tissue featuring collagen deposition and tissue remodelling with negligible cardiomyocyte proliferation. Zebrafish, in contrast, display an extensive regenerative capacity as they are able to restore completely lost cardiac tissue after partial ventricular amputation. Due to the lack of genetic lineage tracing evidence, it is not yet clear if new cardiomyocytes arise from existing contractile cells or from an uncharacterised set of progenitors cells. Nonetheless, several genes and molecules have been shown to participate in this process, some of them being cardiomyocyte mitogens in vitro. Though questions as what are the early signals that drive the regenerative response and what is the relative role of each cardiac cell in this process still need to be answered, the zebrafish is emerging as a very valuable tool to understand heart regeneration and devise strategies that may be of potential value to treat human cardiac disease. Here, we performed a genome-wide transcriptome profile analysis focusing on the early time points of zebrafish heart regeneration and compared our results with those of previously published data. Our analyses confirmed the differential expression of several transcripts, and identified additional genes the expression of which is differentially regulated during zebrafish heart regeneration. We validated the microarray data by conventional and/or quantitative RT-PCR. For a subset of these genes, their expression pattern was analyzed by in situ hybridization and shown to be upregulated in the regenerating area of the heart. The specific role of these new transcripts during zebrafish heart regeneration was further investigated ex vivo using primary cultures of zebrafish cardiomyocytes and/or epicardial cells. Our results offer new insights into the biology of heart regeneration in the zebrafish and, together with future experiments in mammals, may be of potential interest for clinical applications. In order to study zebrafish heart regeneration, a time course experiment was realized where amputated heart regenerating were compared to control heart. Samples in triplicate were extracted at 1, 3, 5 and 7 days post-amputation.

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Interspecies comparison reveals Hmga1 as a key determinator of cardiac regenerative potential

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