Yolk sac-derived fetal macrophages suppress skin fibrosis and contribute to scarless wound healing

Abstract In mice, skin wounds created on embryonic day 13 (E13) regenerate completely, including skin texture restoration; however, after E14, the skin texture does not regenerate, while the dermis regenerates. Furthermore, after E17, neither the texture nor the dermis regenerate, resulting in dermal fibrosis. Currently, there are no detailed reports on the changes in inflammatory cells during this series of changes in the embryonic period. Thus, in this study, we identified the membrane surface markers of fetal macrophages and investigated their potential for use in inhibiting fibrosis. We found that fetal macrophages, which are derived from the yolk sac, accumulate at the wound site until E13 when the skin wound is completely regenerated. Using microarrays, we successfully identified specific markers of fetal macrophages. Furthermore, we demonstrated that transplantation of fetal macrophages into wounds at E14 or in adult animals suppressed fibrosis. These effects were confirmed using microarray results. Recent reports have suggested that yolk sac-derived macrophages are involved in fibrosis in various organs. The utilization of fetal macrophages suggests potential clinical applications in the treatment of fibrotic diseases such as myocardial infarction, pulmonary fibrosis, cirrhosis, and scleroderma, and may lead to innovative therapeutic approaches.