Received date: 19 Oct 2011
Accepted date: 18 Nov 2011
Published date: 01 Dec 2012
Copyright
The Murphy Roths Large (MRL/MpJ) mice provide unique insights into wound repair and regeneration. These mice and the closely related MRL/MpJ-Faslpr/J and Large strains heal wounds made in multiple tissues without production of a fibrotic scar. The precise mechanism of this remarkable ability still eludes researchers, but some data has been generated and insights are being revealed. For example, MRL cells reepithelialize over dermal wound sites faster than cells of other mouse strains. This allows a blastema to develop beneath the protective layer. The MRL mice also have an altered basal immune system and an altered immune response to injury. In addition, MRL mice have differences in their tissue resident progenitor cells and certain cell cycle regulatory proteins. The difficulty often lies in separating the causative differences from the corollary differences. Remarkably, not every tissue in these mice heals scarlessly, and the specific type of wound and priming affect regeneration ability as well. The MRL/MpJ, MRL/MpJ-Faslpr/J, and Large mouse strains are also being investigated for their autoimmune characteristic. Whether the two phenotypes of regeneration and autoimmunity are related remains an enigma.
Key words: MRL; wound healing; regeneration
Ahlke HEYDEMANN . The super super-healing MRL mouse strain[J]. Frontiers in Biology, 2012 , 7(6) : 522 -538 . DOI: 10.1007/s11515-012-1192-4
1 |
Abdullah I, Lepore J J, Epstein J A, Parmacek M S, Gruber P J (2005). MRL mice fail to heal the heart in response to ischemia-reperfusion injury. Wound Repair and Regeneration, 13: 205–208
|
2 |
Adachi M, Watanabe-Fukunaga R, Nagata S (1993). Aberrant transcription caused by the insertion of an early transposable element in an intron of the Fas antigen gene of lpr mice. Proc Natl Acad Sci USA, 90(5): 1756–1760
|
3 |
Alexakis C, Partridge T, Bou-Gharios G (2007). Implication of the satellite cell in dystrophic muscle fibrosis: a self-perpetuating mechanism of collagen overproduction. Am J Physiol Cell Physiol, 293(2): C661–C669
|
4 |
Alleva D G, Kaser S B, Beller D I (1997). Aberrant cytokine expression and autocrine regulation characterize macrophages from young MRL+/+ and NZB/W F1 lupus-prone mice. J Immunol, 159: 5610–5619
|
5 |
Anversa P, Rota M, Urbanek K, Hosoda T, Sonnenblick E H, Leri A, Kajstura J, Bolli R (2005). Myocardial aging–a stem cell problem. Basic Res Cardiol, 100(6): 482–493
|
6 |
Arthur L M, Demarest R M, Clark L, Gourevitch D, Bedelbaeva K, Anderson R, Snyder A, Capobianco A J, Lieberman P, Feigenbaum L, Heber-Katz E (2010). Epimorphic regeneration in mice is p53-independent. Cell Cycle, 9(18): 3667–3673
|
7 |
Ashcroft G S, Yang X, Glick A B, Weinstein M, Letterio J L, Mizel D E, Anzano M, Greenwell-Wild T, Wahl S M, Deng C (1999). Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol, 1(5): 260–266
|
8 |
Baker K L, Daniels S B, Lennington J B, Lardaro T, Czap A, Notti R Q, Cooper O, Isacson O, Frasca S Jr, Conover J C (2006). Neuroblast protuberances in the subventricular zone of the regenerative MRL/MpJ mouse. J Comp Neurol, 498(6): 747–761
|
9 |
Balomenos D, Martin-Caballero J, Garcia M I, Prieto I, Flores J M, Serrano M, Martinez A C (2000). The cell cycle inhibitor p21 controls T-cell proliferation and sex-linked lupus development. Nat Med, 6(2): 171–176
|
10 |
Balu D T, Hodes G E, Anderson B T, Lucki I (2009). Enhanced sensitivity of the MRL/MpJ mouse to the neuroplastic and behavioral effects of chronic antidepressant treatments. Neuropsychopharmacology, 34(7): 1764–1773
|
11 |
Beare A H, Metcalfe A D, Ferguson M W (2006). Location of injury influences the mechanisms of both regeneration and repair within the MRL/MpJ mouse. J Anat, 209(4): 547–559
|
12 |
Bedelbaeva K, Gourevitch D, Clark L, Chen P, Leferovich J M, Heber-Katz E (2004). The MRL mouse heart healing response shows donor dominance in allogeneic fetal liver chimeric mice. Cloning Stem Cells, 6(4): 352–363
|
13 |
Bedelbaeva K, Snyder A, Gourevitch D, Clark L, Zhang X M, Leferovich J, Cheverud J M, Lieberman P, Heber-Katz E (2010). Lack of p21 expression links cell cycle control and appendage regeneration in mice. Proc Natl Acad Sci USA, 107(13): 5845–5850
|
14 |
Blankenhorn E P, Bryan G, Kossenkov A V, Clark L D, Zhang X M, Chang C, Horng W, Pletscher L S, Cheverud J M, Showe L C (2009). Genetic loci that regulate healing and regeneration in LG/J and SM/J mice. Mammalian Genome, 20: 720–733
|
15 |
Blankenhorn E P, Troutman S, Clark L D, Zhang X M, Chen P, Heber-Katz E (2003). Sexually dimorphic genes regulate healing and regeneration in MRL mice. Mamm Genome, 14(4): 250–260
|
16 |
Buckley G, Metcalfe A D, Ferguson M W (2011). Peripheral nerve regeneration in the MRL/MpJ ear wound model. J Anat, 218(2): 163–172
|
17 |
Bulfield G, Siller W G, Wight P A, Moore K J (1984). X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc Natl Acad Sci USA, 81(4): 1189–1192
|
18 |
Chadwick R B, Bu L, Yu H, Hu Y, Wergedal J E, Mohan S, Baylink D J (2007). Digit tip regrowth and differential gene expression in MRL/Mpj, DBA/2, and C57BL/6 mice. Wound Repair and Regeneration, 15: 275–284
|
19 |
Chaudhuri T, Rehfeldt F, Sweeney H L, Discher D E (2010). Preparation of collagen-coated gels that maximize in vitro myogenesis of stem cells by matching the lateral elasticity of in vivo muscle. Methods Mol Biol, 621: 185–202
|
20 |
Cimini M, Fazel S, Fujii H, Zhou S, Tang G, Weisel R D, Li R K (2008). The MRL mouse heart does not recover ventricular function after a myocardial infarction. Cardiovascular pathology: the official journal of the Society for Cardiovascular Pathology 17, 32–39.
|
21 |
Clark L D, Clark R K, Heber-Katz E (1998). A new murine model for mammalian wound repair and regeneration. Clin Immunol Immunopathol, 88(1): 35–45
|
22 |
Colwell A S, Krummel T M, Kong W, Longaker M T, Lorenz H P (2006). Skin wounds in the MRL/MPJ mouse heal with scar. Wound Repair and Regeneration, 14: 81–90
|
23 |
Cowin A J, Brosnan M P, Holmes T M, Ferguson M W (1998). Endogenous inflammatory response to dermal wound healing in the fetal and adult mouse. Developmental Dynamics,212: 385–393.
|
24 |
Cullen M J, Jaros E (1988). Ultrastructure of the skeletal muscle in the X chromosome-linked dystrophic (mdx) mouse. Comparison with Duchenne muscular dystrophy. Acta Neuropathol, 77(1): 69–81
|
25 |
Darby I A, Bisucci T, Pittet B, Garbin S, Gabbiani G, Desmouliere A (2002). Skin flap-induced regression of granulation tissue correlates with reduced growth factor and increased metalloproteinase expression. J Pathol, 197: 117–127
|
26 |
Davis T A, Amare M, Naik S, Kovalchuk A L, Tadaki D (2007). Differential cutaneous wound healing in thermally injured MRL/MPJ mice. Wound Repair and Regeneration, 15: 577–588
|
27 |
Davis T A, Longcor J D, Hicok K C, Lennon G G (2005). Prior injury accelerates subsequent wound closure in a mouse model of regeneration. Cell Tissue Res, 320(3): 417–426
|
28 |
Desmouliere A, Chaponnier C, Gabbiani G (2005). Tissue repair, contraction, and the myofibroblast. Wound Repair and Regeneration, 13: 7–12
|
29 |
Donnelly R P, Levine J, Hartwell D Q, Frendl G, Fenton M J, Beller D I (1990). Aberrant regulation of IL-1 expression in macrophages from young autoimmune-prone mice. J Immunol, 145: 3231–3239
|
30 |
Fawcett J W, Asher R A (1999). The glial scar and central nervous system repair. Brain Res Bull, 49(6): 377–391
|
31 |
Ferguson M W, O'Kane S (2004). Scar-free healing: from embryonic mechanisms to adult therapeutic intervention. Philos Trans R Soc Lond B Biol Sci, 359(1445): 839–850
|
32 |
Fitzgerald J, Rich C, Burkhardt D, Allen J, Herzka A S, Little C B (2008). Evidence for articular cartilage regeneration in MRL/MpJ mice. Osteoarthritis and cartilage / OARS. Osteoarthritis Research Society, 16(11): 1319–1326
|
33 |
Gawronska-Kozak B (2004). Regeneration in the ears of immunodeficient mice: identification and lineage analysis of mesenchymal stem cells. Tissue Eng, 10: 1251–1265
|
34 |
Goss R J (1980). Prospects of regeneration in man. Clin Orthop Relat Res: 270–282
|
35 |
Gourevitch D, Clark L, Chen P, Seitz A, Samulewicz S J, Heber-Katz E (2003). Matrix metalloproteinase activity correlates with blastema formation in the regenerating MRL mouse ear hole model. Developmental Dynamics, 226: 377–387
|
36 |
Gourevitch D L, Clark L, Bedelbaeva K, Leferovich J, Heber-Katz E (2009). Dynamic changes after murine digit amputation: the MRL mouse digit shows waves of tissue remodeling, growth, and apoptosis. Wound Repair and Regeneration, 17: 447–455
|
37 |
Grisel P, Meinhardt A, Lehr H A, Kappenberger L, Barrandon Y, Vassalli G (2008). The MRL mouse repairs both cryogenic and ischemic myocardial infarcts with scar. Cardiovascular Pathology, 17: 14–22
|
38 |
Hampton D W, Seitz A, Chen P, Heber-Katz E, Fawcett J W (2004). Altered CNS response to injury in the MRL/MpJ mouse. Neuroscience, 127(4): 821–832
|
39 |
Han M, Yang X, Taylor G, Burdsal C A, Anderson R A, Muneoka K (2005). Limb regeneration in higher vertebrates: developing a roadmap. Anat Rec B New Anat, 287B(1): 14–24
|
40 |
Harty M, Neff A W, King M W, Mescher A L (2003). Regeneration or scarring: an immunologic perspective. Developmental Dynamics, 226: 268–279
|
41 |
Havran W L, Allison J P (1988). Developmentally ordered appearance of thymocytes expressing different T-cell antigen receptors. Nature, 335(6189): 443–445
|
42 |
Heber-Katz E (1999). The regenerating mouse ear. Semin Cell Dev Biol, 10(4): 415–419
|
43 |
Heber-Katz E, Chen P, Clark L, Zhang X M, Troutman S, Blankenhorn E P (2004a). Regeneration in MRL mice: further genetic loci controlling the ear hole closure trait using MRL and M.m. Castaneus mice. Wound Repair and Regeneration, 12: 384–392
|
44 |
Heber-Katz E, Leferovich J, Bedelbaeva K, Gourevitch D, Clark L (2004b). The scarless heart and the MRL mouse. Philos Trans R Soc Lond B Biol Sci, 359(1445): 785–793
|
45 |
Heber-Katz E, Leferovich J, Bedelbaeva K, Gourevitch D, Clark L (2006). Conjecture: Can continuous regeneration lead to immortality? Studies in the MRL mouse. Rejuvenation Res, 9(1): 3–9
|
46 |
Heydemann A, Ceco E, Lim J E, Hadhazy M, Ryder P, Moran J L, Beier D R, Palmer A A, McNally E M (2009). Latent TGF-beta-binding protein 4 modifies muscular dystrophy in mice. J Clin Invest, 119(12): 3703–3712
|
47 |
Hong Y, Cervantes R B, Tichy E, Tischfield J A, Stambrook P J (2007). Protecting genomic integrity in somatic cells and embryonic stem cells. Mutat Res, 614(1–2): 48–55
|
48 |
Hopkinson-Woolley J, Hughes D, Gordon S, Martin P (1994). Macrophage recruitment during limb development and wound healing in the embryonic and foetal mouse. J Cell Sci, 107(Pt 5): 1159–1167
|
49 |
Ito M R, Ono M, Itoh J, Nose M (2003). Bone marrow cell transfer of autoimmune diseases in a MRL strain of mice with a deficit in functional Fas ligand: dissociation of arteritis from glomerulonephritis. Pathol Int, 53(8): 518–524
|
50 |
Kench J A, Russell D M, Fadok V A, Young S K, Worthen G S, Jones-Carson J, Henson J E, Henson P M, Nemazee D (1999). Aberrant wound healing and TGF-beta production in the autoimmune-prone MRL/+ mouse. Clin Immunol, 92(3): 300–310
|
51 |
Leader B, Leder P (2000). Formin-2, a novel formin homology protein of the cappuccino subfamily, is highly expressed in the developing and adult central nervous system. Mech Dev, 93(1–2): 221–231
|
52 |
Leferovich J M, Bedelbaeva K, Samulewicz S, Zhang X M, Zwas D, Lankford E B, Heber-Katz E (2001). Heart regeneration in adult MRL mice. Proc Natl Acad Sci USA, 98(17): 9830–9835
|
53 |
Li X, Mohan S, Gu W, Baylink D J (2001). Analysis of gene expression in the wound repair/regeneration process. Mammalian Genome, 12: 52–59
|
54 |
Li X, Mohan S, Gu W, Miyakoshi N, Baylink D J (2000). Differential protein profile in the ear-punched tissue of regeneration and non-regeneration strains of mice: a novel approach to explore the candidate genes for soft-tissue regeneration. Biochim Biophys Acta, 1524(2–3): 102–109
|
55 |
Liu H, Ding Q, Yang K, Zhang T, Li G, Wu G (2011). Meta-analysis of systemic lupus erythematosus and the risk of cervical neoplasia. Rheumatology, 50(2): 343–348
|
56 |
Mann C J, Perdiguero E, Kharraz Y, Aguilar S, Pessina P, Serrano A L, Munoz-Canoves P (2011). Aberrant repair and fibrosis development in skeletal muscle. Skeletal muscle 1, 21
|
57 |
Masinde G, Li X, Baylink D J, Nguyen B, Mohan S (2005). Isolation of wound healing/regeneration genes using restrictive fragment differential display-PCR in MRL/MPJ and C57BL/6 mice. Biochem Biophys Res Commun, 330(1): 117–122
|
58 |
Masinde G L, Li X, Gu W, Davidson H, Mohan S, Baylink D J (2001). Identification of wound healing/regeneration quantitative trait loci (QTL) at multiple time points that explain seventy percent of variance in (MRL/MpJ and SJL/J) mice F2 population. Genome Res, 11(12): 2027–2033
|
59 |
McBrearty B A, Clark L D, Zhang X M, Blankenhorn E P, Heber-Katz E (1998). Genetic analysis of a mammalian wound-healing trait. Proc Natl Acad Sci USA, 95(20): 11792–11797
|
60 |
Metcalfe A D, Willis H, Beare A, Ferguson M W (2006). Characterizing regeneration in the vertebrate ear. J Anat, 209(4): 439–446
|
61 |
Michalopoulos G K, DeFrances M C (1997). Liver regeneration. Science, 276(5309): 60–66
|
62 |
Midwood K S, Williams L V, Schwarzbauer J E (2004). Tissue repair and the dynamics of the extracellular matrix. Int J Biochem Cell Biol, 36(6): 1031–1037
|
63 |
Moseley F L, Faircloth M E, Lockwood W, Marber M S, Bicknell K A, Valasek P, Brooks G (2011). Limitations of the MRL mouse as a model for cardiac regeneration. J Pharm Pharmacol, 63(5): 648–656
|
64 |
Namazi M R, Fallahzadeh M K, Schwartz R A (2011). Strategies for prevention of scars: what can we learn from fetal skin? Int J Dermatol, 50(1): 85–93
|
65 |
Naseem R H, Meeson A P, Michael Dimaio J, White M D, Kallhoff J, Humphries C, Goetsch S C, De Windt L J, Williams M A, Garry M G (2007). Reparative myocardial mechanisms in adult C57BL/6 and MRL mice following injury. Physiol Genomics, 30(1): 44–52
|
66 |
Naviaux R K, Le T P, Bedelbaeva K, Leferovich J, Gourevitch D, Sachadyn P, Zhang X M, Clark L, Heber-Katz E (2009). Retained features of embryonic metabolism in the adult MRL mouse. Mol Genet Metab, 96(3): 133–144
|
67 |
Oh Y S, Thomson L E, Fishbein M C, Berman D S, Sharifi B, Chen P S (2004). Scar formation after ischemic myocardial injury in MRL mice. Cardiovascular Pathology, 13: 203–206
|
68 |
Peled Z M, Phelps E D, Updike D L, Chang J, Krummel T M, Howard E W, Longaker M T (2002). Matrix metalloproteinases and the ontogeny of scarless repair: the other side of the wound healing balance. Plast Reconstr Surg, 110(3): 801–811
|
69 |
Peng S L, Madaio M P, Craft J (1996). Systemic autoimmunity in LG/J mice. Immunol Lett, 53(2–3): 153–155
|
70 |
Potter P K, Cortes-Hernandez J, Quartier P, Botto M, Walport M J (2003). Lupus-prone mice have an abnormal response to thioglycolate and an impaired clearance of apoptotic cells. J Immunol, 170: 3223–3232
|
71 |
Rajnoch C, Ferguson S, Metcalfe A D, Herrick S E, Willis H S, Ferguson M W (2003). Regeneration of the ear after wounding in different mouse strains is dependent on the severity of wound trauma. Developmental Dynamics, 226: 388–397
|
72 |
Rao N, Jhamb D, Milner D J, Li B, Song F, Wang M, Voss S R, Palakal M, King M W, Saranjami B, Nye H L D, Cameron J, Stocum D L (2009). Proteomic analysis of blastema formation in regenerating axolotl limbs. BMC Biol, 7(1): 83
|
73 |
Robey T E, Murry C E (2008). Absence of regeneration in the MRL/MpJ mouse heart following infarction or cryoinjury. Cardiovascular Pathology, 17: 6–13
|
74 |
Sacco A, Doyonnas R, Kraft P, Vitorovic S, Blau H M (2008). Self-renewal and expansion of single transplanted muscle stem cells. Nature, 456(7221): 502–506
|
75 |
Sachadyn P, Zhang X M, Clark L D, Naviaux R K, Heber-Katz E (2008). Naturally occurring mitochondrial DNA heteroplasmy in the MRL mouse. Mitochondrion, 8(5–6): 358–366
|
76 |
Saika S (2007). Yin and yang in cytokine regulation of corneal wound healing: roles of TNF-alpha. Cornea, 26(Supplement 1): S70–S74
|
77 |
Santiago-Raber M L, Lawson B R, Dummer W, Barnhouse M, Koundouris S, Wilson C B, Kono D H, Theofilopoulos A N (2001). Role of cyclin kinase inhibitor p21 in systemic autoimmunity. J Immunol, 167: 4067–4074
|
78 |
Shah M, Foreman D M, Ferguson M W (1995). Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring. J Cell Sci, 108(Pt 3): 985–1002
|
79 |
Stocum D L (1984). The urodele limb regeneration blastema. Determination and organization of the morphogenetic field. Differentiation, 27(1–3): 13–28
|
80 |
Stocum, D.L., and Crawford, K. (1987). Use of retinoids to analyze the cellular basis of positional memory in regenerating amphibian limbs. Biochemistry and cell biology, 65: 750–761
|
81 |
Tassava R A (1983). Limb regeneration to digit stages occurs in well-fed adult newts after hypophysectomy. J Exp Zool, 225(3): 433–441
|
82 |
Theofilopoulos A N, Dixon F J (1985). Murine models of systemic lupus erythematosus. Adv Immunol, 37: 269–290
|
83 |
Thuret S, Toni N, Aigner S, Yeo G W, Gage F H (2009). Hippocampus-dependent learning is associated with adult neurogenesis in MRL/MpJ mice. Hippocampus, 19(7): 658–669
|
84 |
Tolba R H, Schildberg F A, Decker D, Abdullah Z, Buttner R, Minor T, von Ruecker A (2010). Mechanisms of improved wound healing in Murphy Roths Large (MRL) mice after skin transplantation. Wound Repair Regen, 18(6): 662–670
|
85 |
Torres V E, Leof E B (2011). Fibrosis, regeneration, and aging: playing chess with evolution. J Am Soc Nephrol, 22(8): 1393–1396
|
86 |
Ueno M, Lyons B L, Burzenski L M, Gott B, Shaffer D J, Roopenian D C, Shultz L D (2005). Accelerated wound healing of alkali-burned corneas in MRL mice is associated with a reduced inflammatory signature. Invest Ophthalmol Vis Sci, 46(11): 4097–4106
|
87 |
Vorotnikova E, McIntosh D, Dewilde A, Zhang J, Reing J E, Zhang L, Cordero K, Bedelbaeva K, Gourevitch D, Heber-Katz E(2010). Extracellular matrix-derived products modulate endothelial and progenitor cell migration and proliferation in vitro and stimulate regenerative healing in vitro. Matrix Biology, 29: 690–700
|
88 |
Wandstrat A, Wakeland E (2001). The genetics of complex autoimmune diseases: non-MHC susceptibility genes. Nat Immunol, 2(9): 802–809
|
89 |
Ward B D, Furman B D, Huebner J L, Kraus V B, Guilak F, Olson S A (2008). Absence of posttraumatic arthritis following intraarticular fracture in the MRL/MpJ mouse. Arthritis Rheum, 58(3): 744–753
|
90 |
Watson M L, Rao J K, Gilkeson G S, Ruiz P, Eicher E M, Pisetsky D S, Matsuzawa A, Rochelle J M, Seldin M F (1992). Genetic analysis of MRL-lpr mice: relationship of the Fas apoptosis gene to disease manifestations and renal disease-modifying loci. J Exp Med, 176(6): 1645–1656
|
91 |
Whitby D J, Ferguson M W (1991). Immunohistochemical localization of growth factors in fetal wound healing. Dev Biol, 147(1): 207–215
|
92 |
Williams B O, Insogna K L (2009). Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone. Journal of Bone and Mineral Research: 24: 171–178
|
93 |
Xu H, Christmas P, Wu X R, Wewer U M, Engvall E (1994). Defective muscle basement membrane and lack of M-laminin in the dystrophic dy/dy mouse. Proc Natl Acad Sci USA, 91(12): 5572–5576
|
94 |
Yu H, Baylink D J, Masinde G L, Li R, Nguyen B, Davidson H M, Xu S, Mohan S (2007). Mouse chromosome 9 quantitative trait loci for soft tissue regeneration: congenic analysis and fine mapping. Wound Repair and Regeneration, 15: 922–927
|
95 |
Yu H, Mohan S, Masinde GL, Baylink D J (2005). Mapping the dominant wound healing and soft tissue regeneration QTL in MRL x CAST. Mammalian Genome, 16: 918–924
|
96 |
Yuan R, Tsaih S W, Petkova S B, Marin de Evsikova C, Xing S, Marion M A, Bogue M A, Mills K D, Peters L L, Bult C J,
|
97 |
Ziv E, Hu D (2011). Genetic variation in insulin/IGF-1 signaling pathways and longevity. Ageing Res Rev, 10(2): 201–204
|
/
〈 | 〉 |