From fish to amphibians to mammals: in search of novel strategies to optimize cardiac regeneration

Abstract

Different vertebrate species have different cardiac regeneration rates: high in teleost fish, moderate in urodele amphibians, and almost negligible in mammals. Regeneration may occur through stem and progenitor cell differentiation or via dedifferentiation with residual cardiomyocytes reentering the cell cycle. In this review, we will examine the ability of zebrafish and newts to respond to cardiac damage with de novo cardiogenesis, whereas rodents and humans respond with a marked fibrogenic response and virtually no cardiomyocyte regeneration. Concerted strategies are needed to overcome this evolutionarily imposed barrier and optimize cardiac regeneration in mammals.

Figure 1.

Schematic representation of stem and progenitor cells in the developing and juvenile/adult rodent heart. CM, cardiomyocytes; EC, endothelial cells; SMC, smooth muscle cells.

Figure 2.

Schematic representation of the hypothetical link between epicardial progenitor cells and the mesoangioblast/pericyte cell population surrounding the coronary vessels. A subpopulation of epicardial cells delaminates from the subendocardial space and migrates to the underlying myocardium using the vascular network as a guide. These progenitors may also be able to generate the intramyocardial clusters of c-kit⁺/Sca-1⁺ stem and progenitor cells that persist into adulthood, but alternative sources of these cells cannot be excluded. CM, cardiomyocytes.

Figure 3.

Myocardial structure in different species. Hematoxylin and eosin staining shows tissue organization in zebrafish (A), axolotl (C), and rat (E) hearts. Vascular-specific GFP expression in transgenic fli1 (friend leukemia integration 1)-GFP zebrafish (Lawson and Weinstein, 2002) or immunostaining with specific antibodies show the distribution of the vascular network in these species. Zebrafish contain epicardial vessels (B, arrows) and endocardial cells that circumvent the cardiomyocytes (B′). Axolotl have no epicardial vessels, whereas endocardial cells expressing the von Willebrand factor (vWf) surround the cardiomyocytes (D). In the rat, the coronary vessels deepen into the myocardium, as shown by staining with antibodies to CD31 (endothelial marker) and SMA (smooth muscle cell marker). (right) Two schematic representations show the positional relationships between cardiomyocytes (CM) and surrounding endothelial (EC) or endocardial (ENC) cells, fibroblasts (F), and pericytes (P). B, B′, D, and F are confocal images of tissue sections. Bars: (A, C, E, and F) 100 µm; (B and D) 50 µm.