The zebrafish heart regenerates after cryoinjury-induced myocardial infarction

Abstract

BackgroundIn humans, myocardial infarction is characterized by irreversible loss of heart tissue, which becomes replaced with a fibrous scar. By contrast, teleost fish and urodele amphibians are capable of heart regeneration after a partial amputation. However, due to the lack of a suitable infarct model, it is not known how these animals respond to myocardial infarction.ResultsHere, we have established a heart infarct model in zebrafish using cryoinjury. In contrast to the common method of partial resection, cryoinjury results in massive cell death within 20% of the ventricular wall, similar to that observed in mammalian infarcts. As in mammals, the initial stages of the injury response include thrombosis, accumulation of fibroblasts and collagen deposition. However, at later stages, cardiac cells can enter the cell cycle and invade the infarct area in zebrafish. In the subsequent two months, fibrotic scar tissue is progressively eliminated by cell apoptosis and becomes replaced with a new myocardium, resulting in scarless regeneration. We show that tissue remodeling at the myocardial-infarct border zone is associated with accumulation of Vimentin-positive fibroblasts and with expression of an extracellular matrix protein Tenascin-C. Electrocardiogram analysis demonstrated that the reconstitution of the cardiac muscle leads to the restoration of the heart function.ConclusionsWe developed a new cryoinjury model to induce myocardial infarction in zebrafish. Although the initial stages following cryoinjury resemble typical healing in mammals, the zebrafish heart is capable of structural and functional regeneration. Understanding the key healing processes after myocardial infarction in zebrafish may result in identification of the barriers to efficient cardiac regeneration in mammals.

High-Resolution Tissue Doppler Imaging of the Zebrafish Heart During Its Regeneration

“…The results of this study differ from previous studies, 5,10 which means that the regenerating heart is still functionally impaired even at 10-14 days after trauma. The 15% of the ventricular myocardium was surgically removed from the apex in this study.…”

“…Researchers have studied how the zebrafish regenerates its heart from cellular, molecular, and genetic viewpoints. [5][6][7][8][9][10] Figure 1 illustrates the time course of zebrafish heart regeneration. 7 Two of the interesting questions that have emerged about zebrafish heart regeneration are (1) how does the zebrafish heart functions during different regeneration phases and (2) do dynamic cardiac functions play any role in heart regeneration?…”

Fast revascularization of the injured area is essential to support zebrafish heart regeneration

“…The zebrafish heart can regenerate after resection, genetic ablation of CMs, and cryoinjury (4)(5)(6)(7)(8). Cryoinjury closely models myocardial infarction because the damaged region is retained after injury, being replaced by a scar that will later be substituted by healthy tissue (5-7).…”

“…Unlike the mammalian heart, the zebrafish heart is able to regenerate following different types of severe insults (4)(5)(6)(7)(8). In zebrafish, the main source of the newly formed CMs is reported to arise by proliferation of preexisting CMs following their dedifferentiation (9,10).…”

The extracellular matrix in myocardial injury, repair, and remodeling

“…Compliant matrices containing elastin promote dedifferentiation, proliferation, and clonal expansion of rat and mouse neonatal cardiomyocytes (140). Second, in fish and amphibians, myocardial regenerative responses seem to be dependent on deposition of a specialized ECM (142). A recent study reported that intramyocardial administration of ECM from healing zebrafish hearts may stimulate regeneration in mouse infarcts (143).…”