Newt immune cells found to help reverse skin fibrosis

A research group including Assistant Professor Kento Hosomi of the Department of Plastic and Reconstructive Surgery, Mie University Faculty of Medicine, and Professor Chikafumi Chiba of the Faculty of Life and Environmental Sciences, University of Tsukuba, discovered that immune cells involved in tissue regeneration in Japanese fire-bellied newts are also involved in the regression of fibrosis that develops in the skin. The researchers found that fibrosis occurring in newt skin regresses naturally and demonstrated that macrophage-like immune cells may be involved in this process. The findings may have applications for human wound healing. The results were published in the August 1 issue of Inflammation and Regeneration.

In mammals, including humans, large skin wounds cannot be completely repaired through regeneration of the original tissue and instead heal with fibrotic scarring. In contrast, newts can regenerate their skin with little or no scar formation.

Organisms with remarkable regenerative abilities, including newts, have attracted attention for their capacity to regenerate tissues, but it has remained unclear how they deal with fibrosis once it develops. It has been known that immune responses play an important role in the healing and fibrosis processes of such organisms.

To investigate this issue, the researchers performed allogeneic skin transplantation in Japanese fire-bellied newts (Cynops pyrrhogaster), a procedure expected to trigger a strong immune response and observed the process in detail.

In humans, such transplants are typically rejected because the immune system recognizes the transplanted skin as non-self, causing the graft to detach and preventing proper wound closure. In contrast, in newts, the transplanted skin did not detach and remained at the graft site. In addition, the researchers observed swelling at the graft site that was not seen when the animals were transplanted with their own skin.

Histological analysis revealed that fibrosis developed beneath the transplanted skin and that this fibrotic tissue was responsible for the swelling of the graft site. Furthermore, the fibrotic tissue formed beneath the skin gradually regressed over time. These observations showed that although newts develop fibrosis in response to non-self-tissue, they are able to subsequently resolve that fibrosis.

The researchers next investigated the mechanism underlying this phenomenon by focusing on cell populations known to be involved in tissue regeneration. Previous studies have shown that reducing macrophage-like cell populations in regenerative urodele amphibians through clodronate treatment inhibits limb regeneration.

Clodronate is a drug used to treat osteoporosis and depletes osteoclasts and macrophages by inhibiting ATP metabolism. When the researchers used clodronate to reduce macrophage-like cell populations in newts, fibrosis still formed in response to transplantation, but the subsequent regression of the fibrotic tissue was delayed. These results suggest that macrophage-like cells (immune cells) involved in tissue regeneration may also play a role in the regression of fibrosis.

Hosomi commented, "Humans cannot fully regenerate tissue after sustaining major injuries, yet newts can. As a plastic surgeon treating many patients with wounds, I have long been interested in how newt wounds heal so cleanly. Through this research, we found evidence that the answer may lie in immune cells.

Building on this discovery, I am now conducting research on wound regeneration and immunity at an overseas laboratory. By advancing this work further, I hope that one day we will be able to develop treatments that allow human wounds to heal as cleanly as those of newts."

Journal Information
Publication: Inflammation and Regeneration
Title: Allogeneic skin transplantation induces transient fibrosis that undergoes spontaneous regression in newts
DOI: 10.1186/s41232-026-00438-0