Transient cell states and signals that play an important role in heart regeneration in zebrafish have been identified by a team of researchers from Germany. These findings contribute to our understanding of the cascade of events leading to heart regeneration and may open up possibilities for enhancing the regenerative capacity of the human heart.

The team was led by Jan Philipp Junker, PhD, and Daniela Panáková, PhD, from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). They published their findings in Nature GeneticsOrigin and function of activated fibroblast states during zebrafish heart regeneration.”

Unlike the human heart, zebrafish hearts can regenerate after injury. For decades, scientists have been unraveling the molecular mechanisms underlying regeneration in zebrafish, with the ultimate goal of unlocking regenerative potential in humans.

In the current study, Junker, Panáková, and colleagues characterized the diversity of activated cell states in the regenerated zebrafish heart using single-cell transcriptomics and spatiotemporal information. “This approach allowed us to identify three transient cell states with fibroblast characteristics (col11a1a, col12a1a, and nppc fibroblasts) that are major sources of known proregenerative genes and also express additional secreted factors with potential proregenerative functions,” the researchers wrote.

Junker believes it makes sense that fibroblasts are responsible for giving the repair signals: “They form right at the site of injury, after all,” he said. To identify the origins of these activated fibroblasts, Junker’s team then produced cell lineage trees using a technique called LINNAEUS, a CRISPR barcoding approach that his lab developed. Using this and other lines of evidence, the researchers identified two sources of temporarily activated fibroblasts: the outer layer of the heart (epicardium) and the inner layer (endocardium).

The nppc fibroblasts were derived from the endocardium, and their activation depended on Wnt signaling. The researchers found that Wnt inhibition leads to a delay in regeneration.

The col11a1a and col12a1a fibroblasts were derived from the epicardium, and the researchers’ analysis predicted that the former were precursors to the latter. But just how important they are became clear when Panáková used a genetic trick to switch off the col12a1a fibroblasts in the zebrafish. The result: no regeneration.

In sum, the work identified specialized transient cell states that contribute to heart regeneration in zebrafish. The researchers now want to look more closely at the genes that are temporarily activated in these cells.

“The pathways that contribute to the regenerative capacity of the zebrafish heart are conserved in humans,” the researchers wrote. “Thus, our analysis may lead us to better understand the limited regenerative capacity of the human heart, while at the same time opening up an exciting strategy to identify potential therapeutic approaches.”

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