Salamander tails and fish fins are oft-cited examples of animals’ ability to regenerate a lost limb or organ. But one mammal—the African spiny mouse—has also emerged as a model of regenerative abilities. In a recent study, Ashley Seifert of the University of Kentucky and his colleagues report that immune cells known as macrophages are essential to the spiny mouse’s capacity to regrow entire anatomical structures. The findings provide insight into how mammals regenerate tissue, and could be relevant to future therapies for wound healing and other conditions.
After an injury, macrophages swoop in to repair tissues and clear debris. In some species, macrophages are crucial to regenerating lost structures and function while in others—including most mammals—they contribute to making scar tissue that simply closes the gap. Seifert and colleagues found that these cells are also key players in the spiny mouse’s ability to re-form complex tissue. The work is a “good characterization of macrophage phenotypes in this new model of regeneration,” says Malcolm Maden of the University of Florida, who was not involved with the study.
Instances of restoring complex anatomical structures, a process dubbed “epimorphic regeneration,” are rare among mammals. “That’s partially a consequence of very few mammalian species being studied,” says Seifert.
When researchers punch a small hole in the ear of a lab mouse (Mus musculus), it heals and forms a scar, which is a thick layer of fibrous connective tissue that replaces skin, muscle and other tissues. But African spiny mice (Acomys cahirinus) regrow the missing chunk, complete with skin, nerves, blood vessels, cartilage and more.
Seifert’s team found that both species had similar proportions and types of circulating white blood cells, including inflammatory cells types such as macrophages and neutrophils. A day after injury, however, neutrophils in lab mice accumulated faster and in greater numbers than they did in spiny mice. These cells also showed greater activity of myeloperoxidase, an enzyme that produces acidic compounds that are antimicrobial and inflammatory.
In spiny mice, macrophages produced large amounts of reactive oxygen species shortly after the injury, and continued to do so over a prolonged period. But activated macrophages—those triggered to respond to the injury—did not infiltrate the mass of cells that eventually regenerated lost tissue. Instead, they remained at the periphery of this mass. When macrophages were depleted from the ear region prior to injury, wounds remained open and regenerative processes were not initiated.
Since macrophages are known to be essential to wound recovery in mammals, and to regeneration in salamanders and fish, their importance in mammalian regeneration isn’t surprising, says Alexander Pinto of The Jackson Laboratory, who was not involved in the study. “When you knock a house down, you need to clear the debris,” he explains. “Macrophages are essentially the bulldozers that do that so you can build a new foundation.”
But their more intriguing role may be as the “contractor that recruits the building crew” to regenerate tissue, he adds. “That’s what some of these data hint at, that they’re more than just clearing the debris.”
Clarifying the roles of different cells could help further research aiming to reduce the buildup of scar tissue after an injury, which can pose problems to movement and other organ functions. “This would impact not only wound healing, but other diseases like pulmonary fibrosis, keloid scarring, etc.,” Seifert says.
Although it’s not yet clear how they might “recruit a building crew,” macrophages that are activated by certain cytokines tend to release chemicals that can trigger reparative processes, study author Jennifer Simkin explains. These signals “can dampen other inflammatory cytokines, and produce other activities in cells,” she says. “For example, they can instruct fibroblasts to make collagen or blood vessels to start growing into the injury to help with wound healing.”
In the long run, these studies could help researchers understand how different macrophage behaviors might promote scarring in some circumstances and regeneration in others. “As we get better tools,” Seifert says, “we might find subtle differences in macrophages that may have an outsize effect whenever they’re present in an injury.”