Scarless skin wound healing in FOXN1 deficient (nude) mice is associated with distinctive matrix metalloproteinase expression

Abstract

Similar to mammalian fetuses FOXN1 deficient (nude) mice are able to restore the structure and integrity of injured skin in a scarless healing process by mechanisms independent of the genetic background. Matrix metalloproteinases (MMPs) are required for regular skin wound healing and the distinctive pattern of their expression has been implicated to promote scarless healing. In this study, we analyzed the temporal and spatial expression patterns of these molecules during the incisional skin wounds in adult nude mice. Macroscopic and histological analyses of skin wounds revealed an accelerated wound healing process, minimal granulation tissue formation and markedly diminished scarring in nude mice. Quantitative RT-PCR (Mmp-2,-3,-8,-9,-10,-12,-13,-14 and Timp-1, -2, -3), Western blots (MMP-13) and gelatin zymography (MMP-9) revealed that MMP-9 and MMP-13 showed a unique, bimodal pattern of up-regulation during the early and late phases of wound healing in nude mice. Immunohistochemically MMP-9 and MMP-13 were generally detected in epidermis during the early phase and in dermis during the late (remodeling) phase. Consistent with these in vivo observations, dermal fibroblasts cultured from nude mice expressed higher levels of type I and III collagen, MMP-9 and MMP-13 mRNA levels and higher MMP enzyme activity than wild type controls. Collectively, these finding suggest that the bimodal pattern of MMP-9 and MMP-13 expression during skin repair process in nude mice could be a major component of their ability for scarless healing.

Concentrations of MMP-9 and TIMP-1 in lip tissue and their impact on cleft lip surgery healing

“…). High expression of MMP-9 during the skin repair process was described on mice models 11,12 . These studies show that high expression of MMP-9 during skin repair process lead to scarless healing.…”

“…MMPs are required for regular skin wound healing and the distinctive pattern of their expression has been implicated in promoting scarless healing. The family of collagens is a major component of the wound extracellular matrix and the major substrate for MMPs action 11 . Type I collagen can be remodeled by several MMPs including MMP-9 (ref.…”

“…Similar results were found in our group of children where healing without scar formation correlated with high levels of MMP-9. High levels of MMP-9 expressions can at least partially explain collagen turnover (production vs degradation) and different kinetics of wound reorganization 11,12 . According to Hosokawa MMP-9 expression and activity implicates the promotion of type I collagen degradation at the site of surgery.…”

FOXN1 Transcription Factor in Epithelial Growth and Wound Healing

“…Interestingly, nude mouse skin has a large population of OCT4-positive dermal cells (52). In vitro studies of primary dermal fibroblasts from nude mice revealed that they produce a higher content of both collagen I and III, although at the same time, they produce active matrix metalloproteinase 9 (MMP-9) and MMP-13, which are completely absent under the wild-type conditions (15). As the dermal part of the skin is responsible for scar formation, Foxn1-deficient mice exhibit a much higher stemness potential of the dermis, and the fibroblasts of nude mice produce large amounts of ECM components but, simultaneously, are able to turn over these components, which prevents ECM restoration.…”

“…It was recently reported that nude (Foxn1-deficient) mice regenerate back skin injuries (15). Taking into consideration that the developmental transition point from scarless to scar-forming skin wound healing coincides with the initiation of Foxn1 expression (16), this makes FOXN1 an attractive signaling molecule to investigate in reparative versus regenerative processes.…”