Accelerated Wound Healing of Alkali-Burned Corneas in MRL Mice Is Associated with a Reduced Inflammatory Signature

Ueno, Masao; Lyons, Bonnie L.; Burzenski, Lisa M.; Gott, Bruce; Shaffer, Daniel J.; Roopenian, Derry C.; Shultz, Leonard D.

doi:10.1167/iovs.05-0548

Cited by 104 publications

(116 citation statements)

References 39 publications

(31 reference statements)

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“…Further studies of this TGFBR1 mutant mouse line may help to elucidate the regulation of wound healing and lead to improved treatments for burns, skin ulcers, or surgical scars through specific regulation of TGFBR1 (31)(32)(33). In addition, ear hole wound healing has been correlated with other soft tissue regeneration traits in MRL/MpJ mice, such as heart, cartilage, cornea, or retinal regeneration (35)(36)(37)(38); thus this TGFBR1 mutant mouse strain may help to understand the balance between remodeling, scar formation, and regeneration in these healing processes.…”

Section: Discussionmentioning

confidence: 99%

Regenerative phenotype in mice with a point mutation in transforming growth factor β type I receptor ( TGFBR1 )

Johnson

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Regeneration of peripheral differentiated tissue in mammals is rare, and regulators of this process are largely unknown. We carried out a forward genetic screen in mice using N -ethyl- N -nitrosourea mutagenesis to identify genetic mutations that affect regenerative healing in vivo. More than 400 pedigrees were screened for closure of a through-and-through punch wound in the mouse ear. This led to the identification of a single pedigree with a heritable, fast, and regenerative wound-healing phenotype. Within 5 wk after ear-punch, a threefold decrease in the diameter of the wound was observed in the mutant mice compared with the wild-type mice. At 22 wk, new cartilage, hair follicles, and sebaceous glands were observed in the newly generated tissue. This trait was mapped to a point mutation in a receptor for TGF-β, TGFBR1 . Mouse embryonic fibroblasts from the affected mice had increased expression of a subset of TGF-β target genes, suggesting that the mutation caused partial activation of the receptor. Further, bone marrow stromal cells from the mutant mice more readily differentiated to chondrogenic precursors, providing a plausible explanation for the enhanced development of cartilage islands in the regenerated ears. This mutant mouse strain provides a unique model to further explore regeneration in mammals and, in particular, the role of TGFBR1 in chondrogenesis and regenerative wound healing.

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Section: Discussionmentioning

confidence: 99%

Regenerative phenotype in mice with a point mutation in transforming growth factor β type I receptor ( TGFBR1 )

Johnson

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Since that time, there have been many reports showing that multiple tissue types in MRL mice display healing responses. These include heart myocardium (Leferovich et al, 2001;Haris Naseem et al, 2007;Alfaro et al, 2008), digits (Chadwick et al, 2007;Gourevitch et al, 2009), articular cartilage (Fitzgerald et al, 2008;Rai et al, 2012), intra-articular fractures (Ward et al, 2008), corneal epithelium (Ueno et al, 2005), CNS stem cells and tissue (Hampton et al, 2004;Baker et al, 2006;Balu et al, 2009;Thuret et al, 2009), central and peripheral nerves (Buckley et al, 2011;Thuret et al, 2012) and myometrial healing (Buhimschi et al, 2010). Further, dorsal skin wounds repaired with skin transplants also show enhanced healing without scarring in MRL (Tolba et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Fine-mapping quantitative trait loci affecting murine external ear tissue regeneration in the LG/J by SM/J advanced intercross line

et al. 2014

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External ear hole closure in LG/J mice represents a model of regenerative response. It is accompanied by the formation of a blastema-like structure and the re-growth of multiple tissues, including cartilage. The ability to regenerate tissue is heritable. An F34 advanced intercross line of mice (Wustl:LG,SM-G34) was generated to identify genomic loci involved in ear hole closure over a 30-day healing period. We mapped 19 quantitative trait loci (QTL) for ear hole closure. Individual gene effects are relatively small (0.08 mm), and most loci have co-dominant effects with phenotypically intermediate heterozygotes. QTL support regions were limited to a median size of 2 Mb containing a median of 19 genes. Positional candidate genes were evaluated using differential transcript expression between LG/J and SM/J healing tissue, function analysis and bioinformatic analysis of single-nucleotide polymorphisms in and around positional candidate genes of interest. Analysis of the set of 34 positional candidate genes and those displaying expression differences revealed over-representation of genes involved in cell cycle regulation/DNA damage, cell migration and adhesion, developmentally related genes and metabolism. This indicates that the healing phenotype in LG/J mice involves multiple physiological mechanisms.

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“…Murphy-Roths-Large (MRL) mice and genetically related strains demonstrate enhanced tissue regeneration after injury to ears, cornea, digit tips, and the heart (Ueno et al 2005;Chadwick et al 2007;Edwards 2008). Histological analysis of MRL ear hole closure is reminiscent of ear regeneration observed in rabbits, cats, and other mammals.…”

mentioning

confidence: 99%

A cellular, molecular, and pharmacological basis for appendage regeneration in mice

et al. 2015

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Regenerative medicine aims to restore normal tissue architecture and function. However, the basis of tissue regeneration in mammalian solid organs remains undefined. Remarkably, mice lacking p21 fully regenerate injured ears without discernable scarring. Here we show that, in wild-type mice following tissue injury, stromal-derived factor-1 (Sdf1) is up-regulated in the wound epidermis and recruits Cxcr4-expressing leukocytes to the injury site. In p21-deficient mice, Sdf1 up-regulation and the subsequent recruitment of Cxcr4-expressing leukocytes are significantly diminished, thereby permitting scarless appendage regeneration. Lineage tracing demonstrates that this regeneration derives from fate-restricted progenitor cells. Pharmacological or genetic disruption of Sdf1-Cxcr4 signaling enhances tissue repair, including full reconstitution of tissue architecture and all cell types. Our findings identify signaling and cellular mechanisms underlying appendage regeneration in mice and suggest new therapeutic approaches for regenerative medicine.

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Accelerated Wound Healing of Alkali-Burned Corneas in MRL Mice Is Associated with a Reduced Inflammatory Signature

Cited by 104 publications

References 39 publications

Regenerative phenotype in mice with a point mutation in transforming growth factor β type I receptor ( TGFBR1 )

Regenerative phenotype in mice with a point mutation in transforming growth factor β type I receptor ( TGFBR1 )

Fine-mapping quantitative trait loci affecting murine external ear tissue regeneration in the LG/J by SM/J advanced intercross line

A cellular, molecular, and pharmacological basis for appendage regeneration in mice

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