How to regenerate a zebrafish heart

Researchers at the Hubrecht Institute have applied new tools to better understand how the zebrafish heart regenerates after injury. The article is published in Developmental Cell this week.

Unlike humans, zebrafish are able to completely repair their heart after injury, for example a myocardial infarction-like event. But how is the fish able to regenerate this injury and, more specifically, what are the initial factors are that push heart muscle cells to start dividing again in order to replace the lost tissue.

To address this question a new method developed at the Hubrecht Institute called tomo-seq was applied to the regenerating heart. Here, a tissue is sectioned across one plane and every single section is barcoded before RNA-sequencing. This allows tracing back transcripts to the section (and thus position in the tissue) from which they originated in order to identify genes that are upregulated in a specific region of the tissue. In the case of the injured zebrafish heart, an injury area, a borderzone with two functionally separate regions and a zone that represents the remote myocardium were identified.

Focusing on the borderzone, which is known to house the majority of proliferating heart muscle cells, we found that bone morphogenetic signaling (BMP) is upregulated. BMP signaling has not been described to be involved in fish heart regeneration so far, and further experiments showed that knock-down of BMP resulted in fewer proliferating muscle cells. On the other hand, when BMP signaling was experimentally upregulated, more heart muscle cells started to divide, in turn increasing the regenerative potential.

In summary, the scientists showed that spatially restricted gene expression can be identified with the tomo-seq method and that this leads to discovery of novel pathways involved in driving the regenerative process, like BMP signaling. Once we fully understand how regeneration occurs in the fish heart, we might be able to extrapolate these findings to humans in order to treat heart disease.

Spatially-resolved genome–wide transcriptional profiling identifies BMP signaling as essential regulator of zebrafish cardiomyocyte regeneration, Kruse, F*, Wu, C-C*,…Bakkers, J., Developmental Cell, in press. *these authors contributed equally