Allogeneic skin transplantation induces transient fibrosis that undergoes spontaneous regression in newts

In humans, large skin defects require tissue transplantation because adult skin lacks full regenerative capacity. However, allogeneic grafts are typically rejected due to strong immune responses, whereas autologous grafts often result in severe fibrosis and permanent scarring. In contrast, regenerative vertebrates such as newts can restore tissues with minimal scarring, suggesting the presence of distinct mechanisms regulating tissue repair. How such organisms respond to immune activation induced by non-self tissue transplantation remains unclear. In this study, we aimed to determine how adult newts respond to allogeneic skin transplantation and to examine whether fibrosis induced under such conditions is sustained or resolved.

We established an allogeneic skin graft model in adult Japanese fire-bellied newts and compared it with autologous grafting. Graft fate, tissue morphology, fibrosis, and immune cell dynamics were analyzed histologically over time. To assess the contribution of macrophage-lineage cells, animals were treated with clodronate liposomes prior to transplantation.

In contrast to mammals, allogeneic grafts did not exhibit typical features of acute rejection and did not show apparent graft loss. Following transplantation, grafts exhibited a characteristic sequence of changes: initial vascular integration, subsequent loss of detectable perfusion, and progressive remodeling of graft appearance. At the donor-host interface, a distinct collagen-rich fibrotic tissue formed, accompanied by marked leukocyte infiltration. This tissue appeared at 2 weeks, reached maximal thickness at 4 weeks, and regressed by 8 weeks. During this period, the graft surface gradually acquired host-like pigmentation, while structural elements of donor tissue remained detectable histologically. Iba1-positive macrophage-lineage cells accumulated within the graft during the fibrotic phase and decreased as the tissue regressed. Depletion of these cells did not prevent fibrosis formation but delayed its regression and prolonged graft thickening.

Allogeneic skin transplantation in adult newts induces a distinct response in which non-self tissue is not completely lost and a collagen-rich fibrotic tissue forms transiently and subsequently undergoes resolution. These findings suggest that fibrosis induced under non-self immune activation is not necessarily a terminal state but may represent a dynamically regulated process capable of resolution.