A potentially important faction within the regenerative medicine community is engaged in trying to understand exactly how highly regenerative species such as salamanders and zebrafish can regenerate organs following injury, and do so repeatedly without scarring. There are also a few examples of adult mammals capable of regenerating a limited number of body parts without scarring, such as African spiny mice and the MRL mouse lineage. It seems plausible that mammalian species still carry much of the machinery of proficient regeneration, but that this machinery is suppressed in some way, possibly because that suppression acts to reduce cancer risk. Evidence in support of that thesis includes the ability of human tumor suppressor ARF to block zebrafish regeneration.
Thus understanding of the fine details of the ways in which highly regenerative species differ from near all mammals might lead to ways to induce limb and organ regrowth in humans. It is still a little early to say whether or not these differences will in fact include anything that could be the basis of a therapy. The differences might be too complex, or too fundamental to easily alter with today’s tools. That said, there is compelling evidence for macrophage behavior to be fundamental to exceptional regeneration. All regeneration is an intricate dance between somatic cells, stem cells and progenitor cells of various types, transient senescent cells, and immune cells, particularly macrophages.
In this context, the research here is an interesting exploration of the activities of macrophages in heart injury in mice and zebrafish. Mice scar rather than regenerate from this type of injury, and the heart is one of the least regenerative organs in mammals. Zebrafish normally regenerate heart injuries without scarring, but this isn’t the case if the injury is inflicted by freezing. These various circumstances give points of comparison to look into the behavior of macrophages in scarring and regeneration, and perhaps suggest lines of investigation that could lead to therapies to prevent scarring in human patients.
Billions of cardiac muscle cells are lost during a heart attack. The human heart cannot replenish these lost cells, so the default mechanism of repair is to form a cardiac scar. While this scar works well initially to avoid ventricular rupture, the scar is permanent, so it will eventually lead to heart failure and the heart will not be able to pump as efficiently as before the damage caused by heart attack.
Zebrafish, a freshwater fish native to South Asia, is known to be able to fully regenerate its heart after damage due to the formation of a temporary scar as new cardiac muscle cells are formed. Researchers have been striving to understand and compare the composition of the cardiac scar in different animals as part of ongoing efforts to investigate whether it can be modulated to become a more transient scar like that of the zebrafish, and therefore potentially avoid heart failure in heart attack patients.
The team focused their efforts on studying the behaviour of macrophages, cells normally associated with inflammation and fighting infection in the body, when exposed to the three post-injury environments. They extracted macrophages from each model to examine their gene expression. In both mouse and fish macrophages, they found that they were showing signs of being directly involved in the creation of the molecules that form part of the cardiac scar, and particularly collagen, which is the main protein involved. “This information is important and quite striking because up to today, only cardiac myofibroblasts have been implicated in directly forming a scar in the heart. By showing that macrophages produce collagen, a key part of scar tissue, this research could lead to new ways to enhance repair after a heart attack.”
Canonical roles for macrophages in mediating the fibrotic response after a heart attack include extracellular matrix turnover and activation of cardiac fibroblasts to initiate collagen deposition. Here we reveal that macrophages directly contribute collagen to the forming post-injury scar. Unbiased transcriptomics shows an upregulation of collagens in both zebrafish and mouse macrophages following heart injury. Adoptive transfer of macrophages, from either collagen-tagged zebrafish or adult mouse collagen donors, enhances scar formation via cell autonomous production of collagen.
In zebrafish, the majority of tagged collagen localises proximal to the injury, within the overlying epicardial region, suggesting a possible distinction between macrophage-deposited collagen and that predominantly laid-down by myofibroblasts. Macrophage-specific targeting of col4a3bpa and cognate col4a1 in zebrafish significantly reduces scarring in cryoinjured hosts. Our findings contrast with the current model of scarring, whereby collagen deposition is exclusively attributed to myofibroblasts, and implicate macrophages as direct contributors to fibrosis during heart repair.