The influence of triiodothyronine on the immune response and extracellular matrix remodeling during zebrafish heart regeneration

Abstract

Damage to the human heart is an irreparable process that results in a permanent impairment in cardiac function. There are, however, a number of vertebrate species including zebrafish (Danio rerio) that can regenerate their hearts following significant injury. In contrast to these regenerative species, mammals are known to have high levels of thyroid hormones, which has been proposed to play a role in this difference in regenerative capacity. However, the mechanisms through which thyroid hormones effect heart regeneration are not fully understood. Here, zebrafish were exposed to exogenous triiodothyronine (T₃) for two weeks and then their hearts were damaged through cryoinjury to investigate the effect of thyroid hormones on ECM remodeling and the components of the immune response during heart regeneration. Additionally, cardiac fibroblasts derived from trout, another species of fish known to display cardiac regenerative capacity, were exposed to T₃ in vitro to analyze any direct effects of T₃ on collagen deposition. It was found that cryoinjury induction results in an increase in myocardial stiffness, but this response was muted in T₃ exposed zebrafish. The measurement of relevant marker gene transcripts suggests that T₃ exposure reduces the recruitment of macrophages to the damaged zebrafish heart immediately following injury but had no effect on the regulation of collagen deposition by cultured trout fibroblasts. These results suggest that T₃ effects both the immune response and ECM remodeling in zebrafish following cardiac injury.