Re-epithelialization of cutaneous wounds in adult zebrafish uses a combination of mechanisms at play during wound closure in embryonic and adult mammals

TLDR

In adult mammals, cutaneous wound re‑epithelialization is a slow, multi‑signalling, multi‑cellular process involving epidermal and other tissues. Live imaging reveals that zebrafish keratinocytes re‑epithelialize wounds by TGFβ‑ and integrin‑driven lamellipodial crawling and long‑range Rho kinase, JNK, and planar‑cell‑polarity‑mediated epithelial rearrangements that recruit cells from the surrounding epidermis, bypassing proliferation and FGF signaling. Adult zebrafish wounds close rapidly and largely independently of other healing processes, making them a useful in‑vivo model for dissecting motogenic versus mitogenic effects on cutaneous re‑epithelialization.

Abstract

Re-epithelialization of cutaneous wounds in adult mammals takes days to complete and relies on numerous signalling cues and multiple overlapping cellular processes that take place both within the epidermis and in other participating tissues. Re-epithelialization of partial- or full-thickness skin wounds of adult zebrafish, however, is extremely rapid and largely independent of the other processes of wound healing. Live imaging after treatment with transgene-encoded or chemical inhibitors reveals that re-epithelializing keratinocytes repopulate wounds by TGFβ- and integrin-dependent lamellipodial crawling at the leading edges of the epidermal tongue. In addition, re-epithelialization requires long-range Rho kinase-, JNK- and, to some extent, planar cell polarity-dependent epithelial rearrangements within the following epidermis, involving radial intercalations, flattening and directed elongations of cells. These rearrangements lead to a massive recruitment of keratinocytes from the adjacent epidermis and make re-epithelialization independent of keratinocyte proliferation and the mitogenic effect of FGF signalling, which are only required after wound closure, allowing the epidermis outside the wound to re-establish its normal thickness. Together these results demonstrate that the adult zebrafish is a valuable in-vivo model for studying, and visualizing, the processes involved in cutaneous wound closure, facilitating the dissection of direct from indirect, and motogenic from mitogenic effects of genes and molecules affecting wound re-epithelialization.