Heart regeneration in the salamander relies on macrophage-mediated control of fibroblast activation and the extracellular landscape

In dramatic contrast to the poor repair outcomes for humans and rodent models such as mice, salamanders and some fish species are able to completely regenerate heart tissue following tissue injury, at any life stage. This capacity for complete cardiac repair provides a template for understanding the process of regeneration and for developing strategies to improve human cardiac repair outcomes. Using a cardiac cryo-injury model we show that heart regeneration is dependent on the innate immune system, as macrophage depletion during early time points post-injury results in regeneration failure. In contrast to the transient extracellular matrix that normally accompanies regeneration, this intervention resulted in a permanent, highly cross-linked extracellular matrix scar derived from alternative fibroblast activation and lysyl-oxidase enzyme synthesis. The activation of cardiomyocyte proliferation was not affected by macrophage depletion, indicating that cardiomyocyte replacement is an independent feature of the regenerative process, and is not sufficient to prevent fibrotic progression. These findings highlight the interplay between macrophages and fibroblasts as an important component of cardiac regeneration, and the prevention of fibrosis as a key therapeutic target in the promotion of cardiac repair in mammals. Macrophages necessary for heart regeneration Heart regeneration in salamanders is dependent on the activation of immune cells. James Godwin of The Jackson Laboratory and MDI Biological Laboratory in the US and colleagues depleted all major organs of a group of Mexican salamanders of macrophages, an immune cell responsible for removing cellular debris. They then injured the salamanders’ heart wall with a liquid nitrogen-cooled probe. Unlike adult mammals, zebrafish and salamanders can normally regenerate their hearts after injury. The team found that macrophage-depleted salamanders were unable to regenerate their hearts compared to a control group. Macrophage depletion led to the formation of a permanent fibrotic extracellular matrix scar. But it did not affect the proliferation of heart muscle cells, indicating that their function is not sufficient to prevent the progression of injury toward fibrosis instead of regeneration.