Abstract
The ratio of matrix metalloproteinases (MMPs) to the tissue inhibitors of metalloproteinases (TIMPs) in wounded tissues strictly control the protease activity of MMPs, and therefore regulate the progress of wound closure, tissue regeneration and scar formation. Some amphibians (i.e. axolotl/newt) demonstrate complete regeneration of missing or wounded digits and even limbs; MMPs play a critical role during amphibian regeneration. Conversely, mammalian wound healing re-establishes tissue integrity, but at the expense of scar tissue formation. The differences between amphibian regeneration and mammalian wound healing can be attributed to the greater ratio of MMPs to TIMPs in amphibian tissue. Previous studies have demonstrated the ability of MMP1 to effectively promote skeletal muscle regeneration by favoring extracellular matrix (ECM) remodeling to enhance cell proliferation and migration. In this study, MMP1 was administered to the digits amputated at the mid-second phalanx of adult mice to observe its effect on digit regeneration. Results indicated that the regeneration of soft tissue and the rate of wound closure were significantly improved by MMP1 administration, but the elongation of the skeletal tissue was insignificantly affected. During digit regeneration, more mutipotent progenitor cells, capillary vasculature and neuromuscular-related tissues were observed in MMP1 treated tissues; moreover, there was less fibrotic tissue formed in treated digits. In summary, MMP1 was found to be effective in promoting wound healing in amputated digits of adult mice.
Highlights
matrix metalloproteinases (MMPs) are activated during the wound healing process and are important regulators of extracellular matrix (ECM) remodeling and tissue regeneration [1,2,3,4]
Our results show that on both 10 days (Fig. 1C–D) and 25 days (Fig. 1E–F) after amputation, there was no significant difference in length between MMP1 treated and non-treated groups (Fig. 1H); the results of hematoxylin and eosin (H&E) staining (Fig. 2) indicated that MMP1 treatment of digit tips accelerated the soft tissue wound healing compared to non-treated control digits 10 days after amputation (Fig. 2B–C)
These results indicate that the wound healing of soft tissues but not the bones was obviously improved with MMP1 administration, suggesting that MMP1 treatment cannot fully regenerate an amputated digit to its original size, it did, have a positive impact on the healing of soft tissues of digits
Summary
MMPs are activated during the wound healing process and are important regulators of ECM remodeling and tissue regeneration [1,2,3,4]. MMP1 expression is suggested to be controlled by cell-collagen interactions [12,13], and presumably aids the migration of tissue progenitor cells by degrading type I and III collagen at the site of injury [4,12]. Recent studies performed both in vitro and in vivo have shown the beneficial impact of MMP1 administration on muscle healing [14,15,16,17]. MMP1 treatment of muscle cells in vitro was shown to increase the migration and myogenic differentiation capacities of the cells [10,14]; transplantation of C2C12 myoblasts in combination with MMP1 into skeletal muscle of MDX/SCID mice, or injection of MMP1 alone to a site of injury showed improved cell migration and increased myofiber formation, as well as reduced fibrotic tissue formation [14]
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