Skin wounds in the MRL/MPJ mouse heal with scar
Department of Surgery, Division of Plastic Surgery, Pediatric Surgery Research Laboratory, Stanford University Medical School, Stanford, California 94305-5148, USA. Wound Repair and Regeneration
(Impact Factor: 2.75).
01/2006; 14(1):81-90. DOI: 10.1111/j.1524-475X.2005.00092.x
Adult MRL/MpJ mice regenerate cartilage during repair of through-and-through ear punch wounds. However, the ability of this mouse strain to heal isolated cutaneous wounds by regeneration or with scar is unknown. The purpose of this study was to characterize the rate of reepithelialization and collagen architecture in dermal wounds from MRL/MpJ mice compared with C57bl/6 and Balb/c strains. Full-thickness incisional (5 mm) and excisional (2 mm diameter) skin wounds were made on the dorsum of 7-week-old MRL/MpJ, C57bl/6, and Balb/c mice. Ear punch wounds were made simultaneously on each animal. Reepithelialization was complete by 48 hours for incisional skin wounds in each strain. All excisional wounds showed incomplete reepithelialization at 24, 48, and 72 hours. At 14 days, all skin wounds had grossly healed. In contrast to the ear wounds made in C57bl/6 and Balb/c mice, MRL/MpJ ear wounds were completely healed by day 28. Dorsal skin wound sections at 14 and 28 days revealed dense collagen deposition and similar degrees of fibrosis between the three strains of mice. In conclusion, in contrast to wound healing in the ear, MRL/MpJ mouse dorsal cutaneous wounds heal similarly to C57bl/6 and Balb/c mice with dermal collagen deposition and scar formation.
Available from: Audrey McAlinden
- "However, at the end of twentieth century, the MRL/MpJ mouse emerged as a classical example of mammalian regeneration since it can heal ear-wounds (Clark et al. 1998; Metcalfe et al. 2006; Fitzgerald et al. 2008; Rai et al. 2012), surgical wounds (Colwell et al. 2006; Heydemann et al. 2012) and articular cartilage lesions (Fitzgerald et al. 2008; Rai et al. 2012). In addition, DBA/1 (Kench et al. 1999; Li et al. 2001; Masinde et al. 2006) and LG/J (Kench et al. 1999; Li et al. 2001; Masinde et al. 2006; Rai et al. 2012) carry similar regenerative abilities to adulthood. "
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ABSTRACT: Tissue regeneration is a complex trait with few genetic models available. Mouse strains LG/J and MRL are exceptional healers. Using recombinant inbred strains from a LG/J and SM/J (non-healer) intercross, we have previously shown a positive genetic correlation between ear-wound healing, knee cartilage regeneration and protection from osteoarthritis. We hypothesize that a common set of genes operates in tissue healing and articular cartilage regeneration. Taking advantage of archived histological sections from recombinant inbred strains, we analyzed expression of candidate genes through branched-chain DNA technology directly from tissue lysates. We determined broad-sense heritability of candidates, Pearson's correlation of candidates with healing phenotypes, and Ward's minimum variance cluster analysis for strains. A bioinformatic assessment of allelic polymorphisms within and near candidate genes was performed. The expression of several candidates was significantly heritable among strains. While several genes correlated with both ear-wound and cartilage healing at a marginal level, the expression of four genes representing DNA repair (Xrcc2, Pcna) and Wnt signaling (Axin2, Wnt16) pathways was significantly positively correlated with both phenotypes. Cluster analysis accurately classified healers and non-healers for seven out of eight strains based on gene expression. Specific sequence differences between LG/J and SM/J were identified as potential causal polymorphisms. Our study suggests a common genetic basis between tissue healing and osteoarthritis susceptibility. Mapping genetic variations causing differences in diverse healing responses in multiple tissues may reveal generic healing processes in pursuit of new therapeutic targets designed to induce or enhance regeneration and potentially protection from osteoarthritis.
Available from: James Monaghan
- "Adult skin is more completely differentiated and adult wounds are open to desiccation and infection, two factors that seriously complicate wound repair. Other promising models of scar-free healing, such as the MRL mouse, which share the ability to regenerate ear punches with rabbits, hares, pikas, cows, pigs and cats , ,  has proven less than perfect when challenged to heal excisional skin wounds ,  casting doubt on the special regenerative powers of this inbred mouse model. "
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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.
Available from: Anthony D Metcalfe
- "We also mapped the immunolocalisation of various factors , e.g. the neural inhibitory extra cellular matrix molecule aggrecan, which may play a role in guiding the direction of nerve growth through the regenerating tissue with the temporal appearance of the regenerating nerve network. Beare et al. (2006) and Colwell et al. (2006) reported that, in both strains of mice, an excisional wound to the dorsal surface of the trunk heals by repair and undergoes scar formation with no evidence of a blastema-like structure. This allowed us to investigate the pattern of reinnervation and revascularisation of the dorsal trunk wound tissue and compare it with that of the ear. "
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ABSTRACT: The MRL/MpJ mouse displays an accelerated ability to heal ear punch wounds without scar formation (whereas wounds on the dorsal surface of the trunk heal with scar formation), offering a rare opportunity for studying tissue regeneration in adult mammals. A blastema-like structure develops and subsequently the structure of the wounded ear is restored, including cartilage, skin, hair follicles and adipose tissue. We sought to assess if the MRL/MpJ strain also possessed an enhanced capacity for peripheral nerve regeneration. Female MRL/MpJ and C57BL/6 mice were wounded with a 2-mm excisional biopsy punch to the centre of each ear and two 4-mm excisional biopsy punches to the dorsal skin. Immunohistochemical dual staining of pan-neurofilament and CD31 markers was used to investigate reinnervation and vascularisation of both the dorsal surface of the trunk and ear wounds. The MRL/MpJ mouse ear exhibited a significantly (P > 0.01) higher density of regenerated nerves than C57BL/6 between 10 and 21 days post-wounding when the blastema-like structure was forming. Unlike dorsal skin wounds, nerve regeneration in the ear wound preceded vascularisation, recapitulating early mammalian development. Immunohistochemical data suggest that factors within the blastemal mesenchyme, such as aggrecan, may direct nerve regrowth in the regenerating ear tissue.
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