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

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

Effects of Hydrogen Peroxide on Wound Healing in Mice in Relation to Oxidative Damage

10.1371/journal.pone.0049215PLoS ONE711

Tensile Properties of the Murine Ventral Vertical Midline Incision

In clinical surgery, the vertical midline abdominal incision is popular but associated with healing failures. A murine model of the ventral vertical midline incision was developed in order to study the healing of this incision type.The strength of the wild type murine ventral abdominal wall in the midline was contained within the dermis; the linea alba made a negligible contribution. Unwounded abdominal wall had a downward trend (nonsignificant) in maximal tension between 12 and 29 weeks of age. The incision attained 50% of its final strength by postoperative day 40. The maximal tension of the ventral vertical midline incision was nearly that of unwounded abdominal wall by postwounding day 60; there was no difference in unwounded vs. wounded maximal tension at postwounding day 120.After 120 days of healing, the ventral vertical midline incision in the wild type mouse was not significantly different from age-matched nonwounded controls. About half of the final incisional strength was attained after 6 weeks of healing. The significance of this work was to establish the kinetics of wild type incisional healing in a model for which numerous genotypes and genetic tools would be available for subsequent study

Auto/paracrine nicotinergic peptides participate in cutaneous stress response to wounding

Restoration of epidermal barrier (epithelialization), is a major component of cutaneous response to stress imposed by wounding. Learning physiologic regulation of epithelialization may lead to novel treatments of chronic wounds. The non-canonical ligands of nicotinic acetylcholine receptors SLURP (secreted mammalian Ly-6/urokinase-type plasminogen activator receptor-related proteins)-1 and -2 are produced by keratinocytes (KCs) and inflammatory cells to augment physiologic responses to non-neuronal acetylcholine, suggesting that they can affect wound epithelialization and inflammation. In this study, recombinant (r)SLURP-1 and -2 exhibited dose dependent effects on migration of cultured KCs, and monoclonal antibodies inactivating auto/paracrine SLURPs in mouse skin delayed wound epithelialization. While effects of rSLURPs on migration were opposite, with rSLURP-1 inhibiting and rSLURP-2 stimulating migration of KCs, each anti-SLURP antibody produced a negative effect on epithelialization in vivo, suggesting their more extensive than regulation of keratinocyte migration involvement in wound repair. Since inflammation plays an important role in stress response to wounding, we measured inflammation biomarkers in wounds treated with anti-SLURP antibodies. Both anti-SLURP-1 and -2 antibodies, or their mixture, caused significant elevation of wound myeloperoxidase, IL-1β, IL-6 and TNFα. Taken together, results of this study demonstrated that SLURP-1 slows crawling locomotion of KCs, and exhibits a strong anti-inflammatory activity in wound tissue. In contrast, SLURP-2 facilitates lateral migration of KCs, but shows a lesser anti-inflammatory capacity. Thus, combined biologic activities of both SLURPs may be required for normal stress response to skin wounding, which favors clinical trial of rSLURP-1 and -2 in wounds that fail to heal

Epithelialization in Wound Healing: A Comprehensive Review

Significance: Keratinocytes, a major cellular component of the epidermis, are responsible for restoring the epidermis after injury through a process termed epithelialization. This review will focus on the pivotal role of keratinocytes in epithelialization, including cellular processes and mechanisms of their regulation during re-epithelialization, and their cross talk with other cell types participating in wound healing. Recent Advances: Discoveries in epidermal stem cells, keratinocyte immune function, and the role of the epidermis as an independent neuroendocrine organ will be reviewed. Novel mechanisms of gene expression regulation important for re-epithelialization, including microRNAs and histone modifications, will also be discussed. Critical Issues: Epithelialization is an essential component of wound healing used as a defining parameter of a successful wound closure. A wound cannot be considered healed in the absence of re-epithelialization. The epithelialization process is impaired in all types of chronic wounds. Future Directions: A comprehensive understanding of the epithelialization process will ultimately lead to the development of novel therapeutic approaches to promote wound closure