Subterranean Fishes of the World

4299

2019

AIM 2019

51

The human heart cannot regenerate following myocardial infarction and instead forms a fibrotic scar that impairs cardiac function. This often leads to heart failure, which is incurable and a major cause of morbidity. Research in the field of cardiac regeneration aims to address this unmet clinical need by stimulating the adult human heart to repair itself, as witnessed in other organisms, like the zebrafish. The Astyanax mexicanus is a uniquely suited model to study cardiac regeneration as it comprises two closely related populations: (1) ‘regenerative’ surface (SF) populations that efficiently replace lost cardiac tissue after injury and (2) the ‘non-regenerative’ Pachόn (PF) cave population that form a scar. Quantitative Trait Locus analysis of the A. mexicanus has identified ITGAM/CD11b as a potential key regulator of cardiac regeneration. ITGAM/CD11b is a leukocyte surface protein that plays an important role in wound repair: it binds to inflamed endothelium to recruit leukocytes to the site of injury so they can clear up debris and coordinate repair and regeneration. RNA sequencing analysis of PF and SF has revealed a number of SNPs in the coding region of ITGAM/CD11b resulting in 2 different proteins, whilst qPCR data shows that PF significantly upregulate ITGAM/CD11b following injury (4-fold increase relative to SF, p<0.005). We thus hypothesised that PF and SF leukocytes bind differently to the endothelium, altering leukocyte recruitment to the wound. Using antibodies and RNAscope, we found striking differences in the spatiotemporal patterns of leukocyte influx at 1 and 3 days following injury. Future studies using flow cytometry will quantify our observations and define the leukocyte subsets that are most impacted by ITGAM/CD11b changes. Understanding how the innate immune responses differ between successful regeneration (SF) and scarring (PF) would be a significant step towards identifying novel therapeutic targets for immunomodulation in heart attack patients.

1

Astyanax Interrnational Meeting