Spiny mice are one of the few mammals with the ability to regenerate tissue, including skin, muscle, and even complex structures such as the tips of their tails, following injury. Researchers have some ideas that might explain why they can regrow tissues while other mammals cannot. “There was once this idea that mammals had evolved an immune system that was keeping them from being able to regenerate,” said Jennifer Simkin, a cell and molecular biologist at Louisiana State University. “The more we studied the immune system, the more we saw that maybe the immune system was acting differently when you could regenerate versus when you couldn't.”
Macrophages are a key piece of immune system-driven regeneration. In a new study, Simkin and Ashley Seifert, a biologist at the University of Kentucky, studied the differences in macrophage behavior during healing. They compared spiny mice, which regenerate ear tissue after punching a hole in their ear, with laboratory mice, which form scar tissue after an identical injury. They found that spiny mouse macrophages secrete factors that induce a regenerative healing response, while macrophages from laboratory mice secrete factors that favor continued inflammation and scarring (1). Their findings, published in Developmental Cell, reveal potential therapeutic targets for enhancing regenerative healing in humans.
“There’s going to be a lot of excitement around this paper because it provides novel information about what controls regeneration and how different macrophage phenotypes affect the outcome of healing,” said Traci Wilgus, an immunologist at The Ohio State University, who was not involved in the study. “There's potential that some of the information that they uncovered here could be used to help wounds heal more efficiently.”
In a previous study, Simkin had shown that macrophages were necessary for both new tissue regeneration and scarring, and that different subsets of macrophages appeared to be active in each process (2). Seifert said, “We wanted to drill a little bit deeper and get a better handle on whether there were different subpopulations of macrophages that were differentially regulating different phases of the injury response and the new tissue building phase of regeneration.”
The researchers started by exploring how bone marrow-derived macrophages from spiny mice and laboratory mice respond to proinflammatory stimuli, specifically interferon gamma (IFNγ) and lipopolysaccharide (LPS), by measuring the cytokines they secrete.
Macrophages from both spiny and laboratory mice increased the secretion of proinflammatory cytokines following IFNγ + LPS stimulation. However, the level of increase in these cytokines was significantly higher in macrophages from laboratory mice than in macrophages from spiny mice, which could potentially lead to more inflammation-driven fibrosis or scar formation in the former.
Macrophages from spiny mice stimulated with IFNγ + LPS secreted distinct factors like platelet-derived growth factor A (PDGFA), lactotransferrin (LTF), and vascular endothelial growth factor C (VEGFC), which promote a regenerative, rather than fibrotic, healing process. These factors were largely absent in macrophages from laboratory mice. PDGFA and VEGFC participate in cell proliferation and blood vessel formation, while LTF has anti-inflammatory properties. “[Finding] lactotransferrin was surprising because it's much more prominent in secretions like breast milk,” said Seifert. “The fact that it's being deployed in a tissue repair context means it possibly has an antioxidant effect to protect cells.”
A receptor-ligand analysis conducted to identify potential interactions between macrophage-secreted factors and other cell types in the healing tissue of spiny mice and laboratory mice revealed that fibroblasts from spiny mice expressed the receptors for PDGFA, LTF, and VEGFC during peak inflammation five days after an ear punch injury. This suggests that these macrophage-derived factors can directly influence fibroblasts during early healing stages, potentially enhancing the regenerative response. This specific interaction was not observed in fibroblasts from laboratory mice, indicating a unique mechanism in spiny mice that may contribute to its regenerative capabilities.
Lastly, the researchers used a blocking antibody to inhibit the interaction between VEGFC and its receptors and then observed the effects on tissue regeneration after an ear punch. Mice that received the VEGFC-blocking antibody had a significant delay in wound closure rate, but eventually regenerated the tissue. “I'm looking forward to seeing what they do next because I think they could do more detailed studies to understand the role of VEGFC in the process of regeneration,” said Wilgus. “There are probably other important factors or other important cell types that need to be considered.”
A long-term goal of Simkin’s research is to use macrophages as therapeutics to foster a regenerative environment. “It's pretty common in cancer therapies to try to tweak the macrophage to change the environment and reduce cancer spreading,” she said. “If we can do the same for wound healing, we'd be able to target macrophages and change the outcome of an injury away from fibrosis and toward regeneration.”
Correction: June 24, 2024: An earlier version of the story listed the incorrect dek. The dek has been updated to the correct one.
References
- Simkin, J. et al. Tissue-resident macrophages specifically express Lactotransferrin and Vegfc during ear pinna regeneration in spiny mice. Dev Cell 59, 496-516.e6 (2024).
- Simkin, J., Gawriluk, T. R., Gensel, J. C. & Seifert, A. W. Macrophages are necessary for epimorphic regeneration in African spiny mice. eLife 6, e24623
