Skin Regeneration in Adult Axolotls: A Blueprint for Scar-Free Healing in Vertebrates

Abstract

While considerable progress has been made towards understanding the complex processes and pathways that regulate human wound healing, regenerative medicine has been unable to develop therapies that coax the natural wound environment to heal scar-free. The inability to induce perfect skin regeneration stems partly from our limited understanding of how scar-free healing occurs in a natural setting. Here we have investigated the wound repair process in adult axolotls and demonstrate that they are capable of perfectly repairing full thickness excisional wounds made on the flank. In the context of mammalian wound repair, our findings reveal a substantial reduction in hemostasis, reduced neutrophil infiltration and a relatively long delay in production of new extracellular matrix (ECM) during scar-free healing. Additionally, we test the hypothesis that metamorphosis leads to scarring and instead show that terrestrial axolotls also heal scar-free, albeit at a slower rate. Analysis of newly forming dermal ECM suggests that low levels of fibronectin and high levels of tenascin-C promote regeneration in lieu of scarring. Lastly, a genetic analysis during wound healing comparing epidermis between aquatic and terrestrial axolotls suggests that matrix metalloproteinases may regulate the fibrotic response. Our findings outline a blueprint to understand the cellular and molecular mechanisms coordinating scar-free healing that will be useful towards elucidating new regenerative therapies targeting fibrosis and wound repair.

Macrophages are required for adult salamander limb regeneration

“…More recent studies in the axolotl reported the recruitment of neutrophils in deep tissue wounds but not in regenerating limbs (8,31). By contrast, using a range of methods, the present study confirms the active involvement of macrophages within the regenerating axolotl limb.…”

“…S9). α-Smooth muscle actin (α-SMA) is an established marker for differentiated myofibroblasts displaying subepithelial localization (31)(32)(33) in several species. Macrophage-depleted animals showed increased numbers of α-SMA-positive cells compared with the normally low levels observed in control animals at 20 dpa (Fig.…”

Effect of Bone Marrow Derived Mesenchymal Stem Cells on Healing of Induced Full-Thickness Skin Wounds in Albino Rat

“…After three weeks, it became thicker and was arranged in different directions in a network like manner that mimic control skin. These findings might be attributed to the initial deposition of thin collagen fibrils (type III) that were later resorbed and replaced with thicker fibrils (type I) aligned with stress lines indicating maturity of wound (22,25,26). Eventually, in delayed healing of wounds in systemically treated group after three weeks, collagen fibres were still relatively thin and oriented parallel to the skin indicating delayed healing.…”

“…This might facilitate earlier progress to the next phases of wound healing as reduced inflammation promotes regeneration rather than scarring (22). This notion might explain wound regeneration in BMSCs-treated groups and scar formation in non treated group.…”

“…It was also suggested that BMSCs could recruit more fibroblasts from the surrounding tissues through chemotaxis (22)(23)(24).…”