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

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. Overall design: Tg(nppa:mCitrine) positive cells showing high mCitrine expression were isolated from cyoinjured zebrafish hearts (7 days post injury). From 12 hmga1a-/- mutants hearts, 768 cells were isolated. From 12 hmga1a+/+ wild-type hearts, 768 cells were isolated. All cells were sent for single cell RNA sequencing, but one wild-type plate failed during sequencing and was not used for further analysis.