Abstract
SummaryAlthough Astyanax mexicanus surface fish regenerate their hearts after injury, their Pachón cave-dwelling counterparts cannot and, instead, form a permanent fibrotic scar, similar to the human heart. Myocardial proliferation peaks at similar levels in both surface fish and Pachón 1 week after injury. However, in Pachón, this peak coincides with a strong scarring and immune response, and ultimately, cavefish cardiomyocytes fail to replace the scar. We identified lrrc10 to be upregulated in surface fish compared with Pachón after injury. Similar to cavefish, knockout of lrrc10 in zebrafish impairs heart regeneration without affecting wound cardiomyocyte proliferation. Furthermore, using quantitative trait locus (QTL) analysis, we have linked the degree of heart regeneration to three loci in the genome, identifying candidate genes fundamental to the difference between scarring and regeneration. Our study provides evidence that successful heart regeneration entails a delicate interplay between cardiomyocyte proliferation and scarring.
Highlights
Complete regeneration of the adult heart after injury is a feature exclusive to a limited number of species, including vertebrates such as the zebrafish and salamander (Borchardt and Braun, 2007; Poss et al, 2002; Witman et al, 2011)
To date, research on fish heart regeneration has not yet led to significant breakthroughs in the search for therapies achieving human heart regeneration. This is largely because the use of candidate gene approaches is biased toward the identification of genes and molecular mechanisms already predicted to affect the ability of the heart to regenerate
We show that Astyanax mexicanus cavefish and surface fish respond differently to cardiac injury
Summary
Complete regeneration of the adult heart after injury is a feature exclusive to a limited number of species, including vertebrates such as the zebrafish and salamander (Borchardt and Braun, 2007; Poss et al, 2002; Witman et al, 2011). To date, research on fish heart regeneration has not yet led to significant breakthroughs in the search for therapies achieving human heart regeneration This is largely because the use of candidate gene approaches is biased toward the identification of genes and molecular mechanisms already predicted to affect the ability of the heart to regenerate. Comparing the natural regenerative and scarring response within the same species would avoid confounding physiological factors and allow identifying the key mechanisms driving regeneration, aiding the translation of advances in our understanding of fish heart regeneration to human. We show that Astyanax mexicanus cavefish and surface fish respond differently to cardiac injury This allows us to compare the regenerative and scarring response within one species and provides the opportunity to link the capacity for heart regeneration directly to the genome using forward genetic screening
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