Researchers Uncover Key Protein in Tadpole Tail Regeneration

Researchers from the University of Tokyo have identified a protein known as c1qtnf3 that plays a critical role in the regeneration of tadpole tails. This discovery, published in the Proceedings of the National Academy of Sciences on November 17, 2025, reveals how this protein influences macrophages, shifting them from immune functions to roles that promote tissue regeneration.

Tadpoles of the species Xenopus laevis possess remarkable regenerative abilities, allowing them to regrow fully functional tails complete with spinal cords and muscles. Central to this process are stem cells, which activate during regeneration. However, studying these cells has proven challenging due to their limited numbers.

Researchers Sumika Kato, Takeo Kubo, and Taro Fukazawa developed a method to enrich tissue stem cells, enabling them to analyze gene expression in these cells during tail regeneration. Utilizing single-cell RNA sequencing, they identified various cell types, focusing on putative muscle stem cells that exhibited higher levels of c1qtnf3 compared to other cells.

To explore the role of c1qtnf3 in tail regeneration, the team conducted “knockdown” experiments, effectively blocking the gene’s activity. “The knockdown of c1qtnf3 resulted in impaired tail regeneration,” Kato noted, indicating the protein’s essential role in this process. The experiments also revealed a reduction in macrophage numbers at the tail stump in the modified tadpoles, suggesting that c1qtnf3 is crucial for macrophage function.

Linking Stem Cells and Macrophages

This initial finding led to the hypothesis that macrophages, influenced by muscle stem cells via c1qtnf3, significantly contribute to the regeneration process. To test this theory, the researchers utilized another gene, neutrophil cytosolic factor 1, which is known to enhance macrophage function.

Kato expressed excitement at the results, stating, “When I found that forced expression of the gene, and consequently rising macrophage numbers, rescued tail regeneration in tadpoles, it felt like the dots connected.” This research suggests a mechanism whereby putative muscle stem cells secrete c1qtnf3, promoting macrophage accumulation in the tail stub, crucial for facilitating tail regeneration.

The implications of this study extend beyond tadpoles. Understanding the cellular and molecular mechanisms involved in regeneration could open avenues for potential applications in mammals, including regenerative medicine.

Moving forward, the researchers plan to investigate how macrophages enhance regeneration under the influence of c1qtnf3 and to delve deeper into the specific cellular interactions within regenerating tissues. As they continue this line of inquiry, their findings could contribute significantly to advancements in regenerative therapies for various medical conditions.

For more information, refer to the study titled “Putative muscle cells promote Xenopus tail regeneration by modifying macrophage function via c1qtnf3,” published in the Proceedings of the National Academy of Sciences.