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Organ and Appendage Regeneration in the Axolotl

  • Johanna E. Farkas
  • Piril Erler
  • Polina D. Freitas
  • Alexandra E. Sweeney
  • James R. MonaghanEmail author
Chapter

Abstract

Regeneration is a remarkable feat of biology. It requires an organ system – most often consisting of many different cell types – to stop its specialized function and step back in ontological time. Regeneration overcomes the general understanding that development is a one-way street. We now know that there is great variability in regeneration capacity across phylogeny, likely because animals need to have some mechanism in place to survive injuries or diseases that it will encounter. Some animals, including humans, meet this need by closing the wound as quickly as possible and making due with the deficit. Other animals, such as the axolotl described here, instead regenerate the damaged or missing tissue.

Ambystoma mexicanum, commonly known as the axolotl, is uncommon among vertebrates because of its superior regenerative abilities. References of their unique abilities cross from the scientific to the main stream media, but they are also useful animals for understanding the mechanisms that regulate regeneration. As axolotls are tetrapods that can breed all year-round and accept grafts between adults, they possess some major advantages that make them uniquely suited to be animal models of regeneration. In terms of appendage regeneration, there is currently a lack of animal models for complex regeneration. The two dominant models are zebrafish, which regenerate caudal fins throughout life, and Xenopus frogs, which can regenerate limbs and tails early in development. Although these systems have provided important insights into vertebrate regeneration, the axolotl limb is particularly well suited to study adult appendage regeneration. Axolotls are capable of regenerating complete adult limbs that are morphologically similar to human limbs using endochondral ossification. In contrast, the zebrafish dermal caudal fin skeleton has no mammalian counterpart, and the fin skeleton regenerates by direct ossification from mature osteocytes (Sousa et al. Development, 138(18):3897–3905, 2011; Knopf et al. Dev Cell 20(5):713–724, 2011). Xenopus regenerates early in development, but its ability to regenerate patterned skeletal structures is absent in adulthood. Therefore, the axolotl is among the best vertebrate models for adult joint regeneration.

Although axolotls have been studied for almost 200 years, only recently have technological advances helped revive the axolotl into a model organism in modern regeneration biology (Voss et al. Cold Spring Harbor Protoc 2009(8), 2009). The axolotl is becoming a chosen model for regenerative biology because it can regenerate more completely than any other vertebrate in the majority of organs studied. Modern genomic tools are available including microarray analysis (Monaghan et al. J Neurochem 101(1):27–40, 2007; BMC Biol 7, 2009; Biol Open. 2012; Campbell et al. Dev Dyn: An Off Publ Am Assoc Anat 240(7):1826–1840, 2011), RNAseq (Monaghan et al. BMC Biol 7, 2009; Stewart et al. PLoS Comput Biol 9(3):e1002936, 2013; Knapp et al. PLoS One 8(5):e61352, 2013), a genomic map (Smith et al. Genetics 171(3):1161–1171, 2005a), genomic sequence data (Smith et al. BMC Genomics 10:19, 2009), and bioinformatic databases (Smith et al. BMC Genomics 6:181, 2005b). Functional testing of genes is also available through the generation of transgenics (Sobkow et al. Dev Biol 290(2):386–397, 2006; Monaghan and Maden, Dev Biol 368(1):63–75, 2012a; Khattak et al. Nat Protoc 9(3):529–540, 2014; Whited et al. Proc Natl Acad Sci U S A 109(34):13662–13667, 2012), knock-down of genes by morpholinos (Schnapp et al. Development 132(14):3243–3253, 2005; Zhu et al. Dev Biol 370(1):42–51, 2012), over-expression of genes by electroporation (Mercader et al. Development 132(18):4131–4142, 2005) and viruses (Whited et al. Development 140(5):1137–1146, 2013; Khattak et al. BMC Dev Biol 13:17, 2013), and cell tracking by tissue grafting between GFP and white axolotls (Nacu et al. Cold Spring Harbor Protoc 2009(8), 2009). With this array of modern tools, married with the qualities that have made the axolotl a subject of research for hundreds of years, the axolotl system has become a powerful model to dissect the mechanisms that regulate development and regeneration.

Here, we will highlight what is known about the axolotl’s regenerative abilities and discuss the mechanisms that regulate regeneration of each organ system. It is generally assumed that the axolotl has the ability to regenerate most if not all of its tissues, but a survey of tissue regeneration has yet to be performed in this animal model. We will focus upon the regenerative capacity of the axolotl, but it is necessary to include examples of regeneration in the newt, Xenopus laevis, and zebrafish because in some aspect these species have been studied in more detail than in the axolotl model.

Keywords

Axolotl Ambystoma mexicanum Cardiac regeneration Nervous system Limb regeneration Spinal cord Wound healing Immune system Extracellular matrix 

References

  1. Adzick NS, Longaker MT (1992) Scarless fetal healing. Therapeutic implications. Ann Surg 215(1):3–7PubMedPubMedCentralCrossRefGoogle Scholar
  2. Adzick NS, Lorenz HP (1994) Cells, matrix, growth factors, and the surgeon. The biology of scarless fetal wound repair. Ann Surg 220(1):10–18PubMedPubMedCentralCrossRefGoogle Scholar
  3. Allan CH et al (2006) Tissue response and Msx1 expression after human fetal digit tip amputation in vitro. Wound Repair Regen 14(4):398–404PubMedCrossRefGoogle Scholar
  4. Arvidsson A et al (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8(9):963–970PubMedCrossRefGoogle Scholar
  5. Bellayr IH, Walters TJ, Li Y (2010) Scarless wound healing. J Am Coll Certif Wound Spec 2(2):40–43Google Scholar
  6. Bertolotti E, Malagoli D, Franchini A (2013) Skin wound healing in different aged Xenopus laevis. J Morphol 274(8):956–964PubMedCrossRefGoogle Scholar
  7. Bois AD, Beaumont JD (1927) Intersexualité phénotypique dans la gonade mâle du triton. C R Soc Biol 97:1323–1324Google Scholar
  8. Borgens RB (1982) Mice regrow the tips of their foretoes. Science 217(4561):747–750PubMedCrossRefGoogle Scholar
  9. Buckley G et al (2012) Denervation affects regenerative responses in MRL/MpJ and repair in C57BL/6 ear wounds. J Anat 220(1):3–12PubMedPubMedCentralCrossRefGoogle Scholar
  10. Butler EG (1935) Studies on limb regeneration in X-rayed amblystoma larvae. Anat Rec 62(3):295–307CrossRefGoogle Scholar
  11. Butler EG, O’Brien JP (1942) Effects of localized x-radiation on regeneration of the urodele limb. Anat Rec 84(4):407–413CrossRefGoogle Scholar
  12. Butler EG, Ward MB (1965) Reconstitution of the spinal cord following ablation in urodele larvae. J Exp Zool 160(1):47–65PubMedCrossRefGoogle Scholar
  13. Butler EG, Ward MB (1967) Reconstitution of the spinal cord after ablation in adult Triturus. Dev Biol 15(5):464–486PubMedCrossRefGoogle Scholar
  14. Campbell LJ et al (2011) Gene expression profile of the regeneration epithelium during axolotl limb regeneration. Dev Dyn: An Off Publ Am Assoc Anat 240(7):1826–1840CrossRefGoogle Scholar
  15. Cano-Martinez A et al (2010) Functional and structural regeneration in the axolotl heart (Ambystoma mexicanum) after partial ventricular amputation. Arch Cardiol Mex 80(2):79–86PubMedGoogle Scholar
  16. Chalkley DT (1954) A quantitative histological analysis of forelimb regeneration in triturus viridescens. J Morphol 94(1):21–70CrossRefGoogle Scholar
  17. Chen G, Robert J (2011) Antiviral immunity in amphibians. Viruses 3(11):2065–2086PubMedPubMedCentralCrossRefGoogle Scholar
  18. Chernoff EA (1996) Spinal cord regeneration: a phenomenon unique to urodeles? Int J Dev Biol 40(4):823–831PubMedGoogle Scholar
  19. Chernoff EA et al (2000) Matrix metalloproteinase production in regenerating axolotl spinal cord. Wound Repair Regen 8(4):282–291PubMedCrossRefGoogle Scholar
  20. Chernoff EA et al (2003) Urodele spinal cord regeneration and related processes. Dev Dyn 226(2):295–307PubMedCrossRefGoogle Scholar
  21. Chow A, Brown BD, Merad M (2011) Studying the mononuclear phagocyte system in the molecular age. Nat Rev Immunol 11(11):788–798PubMedCrossRefGoogle Scholar
  22. Clarke JD, Alexander R, Holder N (1988) Regeneration of descending axons in the spinal cord of the axolotl. Neurosci Lett 89(1):1–6PubMedCrossRefGoogle Scholar
  23. Collucci V (1891) Sulla rigenerazione parziale deell’occhio nei tritoni: Isogenesi esvilluppo-Studio seprimentale. Mem R Accad Sci lst Bologna Ser 5(1):593–629Google Scholar
  24. da Silva SM, Gates PB, Brockes JP (2002) The newt ortholog of CD59 is implicated in proximodistal identity during amphibian limb regeneration. Dev Cell 3(4):547–555PubMedCrossRefGoogle Scholar
  25. Davis BM et al (1990) Time course of salamander spinal cord regeneration and recovery of swimming: HRP retrograde pathway tracing and kinematic analysis. Exp Neurol 108(3):198–213PubMedCrossRefGoogle Scholar
  26. Desmouliere A, Chaponnier C, Gabbiani G (2005) Tissue repair, contraction, and the myofibroblast. Wound Repair Regen 13(1):7–12PubMedCrossRefGoogle Scholar
  27. Echeverri K, Tanaka EM (2005) Proximodistal patterning during limb regeneration. Dev Biol 279(2):391–401PubMedCrossRefGoogle Scholar
  28. Egar M, Singer M (1972) The role of ependyma in spinal cord regeneration in the urodele, Triturus. Exp Neurol 37(2):422–430PubMedCrossRefGoogle Scholar
  29. Eguchi G (1963) Electron microscopic studies on lens regeneration. Embryologia 8(1):45–62CrossRefGoogle Scholar
  30. Eriksson PS et al (1998) Neurogenesis in the adult human hippocampus. Nat Med 4(11):1313–1317PubMedCrossRefGoogle Scholar
  31. Fawcett JW, Asher RA (1999) The glial scar and central nervous system repair. Brain Res Bull 49(6):377–391PubMedCrossRefGoogle Scholar
  32. Fei JF et al (2014) CRISPR-mediated genomic deletion of Sox2 in the axolotl shows a requirement in spinal cord neural stem cell amplification during tail regeneration. Stem Cell Rep 3(3):444–459CrossRefGoogle Scholar
  33. Fellah JS et al (1989) Ontogeny of immunoglobulin expression in the Mexican axolotl. Development 107(2):253–263PubMedGoogle Scholar
  34. Ferri A et al (2013) Sox2 is required for embryonic development of the ventral telencephalon through the activation of the ventral determinants Nkx2.1 and Shh. Development 140(6):1250–1261PubMedCrossRefGoogle Scholar
  35. Ferris DR et al (2010) Ex vivo generation of a functional and regenerative wound epithelium from axolotl (Ambystoma mexicanum) skin. Dev Growth Differ 52(8):715–724PubMedCrossRefGoogle Scholar
  36. Flament SP et al (2009) Lifelong testicular differentiation in Pleurodeles waltl (Amphibia, Caudata). Reprod Biol Endocrinol 7:21Google Scholar
  37. Flink IL (2002) Cell cycle reentry of ventricular and atrial cardiomyocytes and cells within the epicardium following amputation of the ventricular apex in the axolotl, Amblystoma mexicanum: confocal microscopic immunofluorescent image analysis of bromodeoxyuridine-labeled nuclei. Anat Embryol (Berl) 205(3):235–244CrossRefGoogle Scholar
  38. Foret JE (1970) Regeneration of larval urodele limbs containing homoplastic transplants. J Exp Zool 175(3):297–321PubMedCrossRefGoogle Scholar
  39. Gaete M et al (2012) Spinal cord regeneration in Xenopus tadpoles proceeds through activation of Sox2-positive cells. Neural Dev 7:13PubMedPubMedCentralCrossRefGoogle Scholar
  40. Garavini C (1977) Regeneration of the spleen in Triturus cristatus. Arch Ital Anat Embriol 82(4):319–325PubMedGoogle Scholar
  41. Ghosh S, Thorogood P, Ferretti P (1994) Regenerative capability of upper and lower jaws in the newt. Int J Dev Biol 38(3):479–490PubMedGoogle Scholar
  42. Godwin JW, Rosenthal N (2014) Scar-free wound healing and regeneration in amphibians: immunological influences on regenerative success. Differentiation 87(1–2):66–75PubMedCrossRefGoogle Scholar
  43. Godwin JW, Pinto AR, Rosenthal NA (2013) Macrophages are required for adult salamander limb regeneration. Proc Natl Acad Sci U S A 110(23):9415–9420PubMedPubMedCentralCrossRefGoogle Scholar
  44. Goldhamer DJ, Tassava RA (1987) An analysis of proliferative activity in innervated and denervated forelimb regenerates of the newt. Notophthalmus Viridescens Dev 100(4):619–628Google Scholar
  45. Goldhamer DJ, Tomlinson BL, Tassava RA (1992) Ganglia implantation as a means of supplying neurotrophic stimulation to the newt regeneration blastema: cell-cycle effects in innervated and denervated limbs. J Exp Zool 262(1):71–80PubMedCrossRefGoogle Scholar
  46. Goss RJ, Stagg MW (1958) Regeneration of lower jaws in adult newts. J Morphol 102(2):289–309CrossRefGoogle Scholar
  47. Grubb RB (1975) An autoradiographic study of the origin of intestinal blastemal cells in the newt, Notophthalmus viridescens. Dev Biol 47(1):185–195PubMedCrossRefGoogle Scholar
  48. Gurtner GC et al (2008) Wound repair and regeneration. Nature 453(7193):314–321PubMedCrossRefGoogle Scholar
  49. Harty M et al (2003) Regeneration or scarring: an immunologic perspective. Dev Dyn 226(2):268–279PubMedCrossRefGoogle Scholar
  50. Heberlein JML (1930) Uber regeneration innerer organe beim axolotl. G. Fischer, Thüringische Landesuniversität JenaGoogle Scholar
  51. Holtzer SW (1956) The inductive activity of the spinal cord in urodele tail regeneration. J Morphol 99(1):1–39CrossRefGoogle Scholar
  52. Huang TY et al (2015) Cooperative regulation of substrate stiffness and extracellular matrix proteins in skin wound healing of axolotls. Biomed Res Int 2015:712546PubMedPubMedCentralGoogle Scholar
  53. Hui SP et al (2013) Expression pattern of Nogo-A, MAG, and NgR in regenerating urodele spinal cord. Dev Dyn 242(7):847–860PubMedCrossRefGoogle Scholar
  54. Illingworth CM (1974) Trapped fingers and amputated finger tips in children. J Pediatr Surg 9(6):853–858PubMedCrossRefGoogle Scholar
  55. Imokawa Y, Brockes JP (2003) Selective activation of thrombin is a critical determinant for vertebrate lens regeneration. Curr Biol 13(10):877–881PubMedCrossRefGoogle Scholar
  56. Iten L, Bryant S (1973) Forelimb regeneration from different levels of amputation in the newt, Notophthalmus viridescens: length, rate, and stages. Wilhelm Roux’ Archiv für Entwicklungsmechanik der Organismen 173(4):263–282CrossRefGoogle Scholar
  57. Iten LE, Bryant SV (1976) Stages of tail regeneration in the adult newt, Notophthalmus viridescens. J Exp Zool 196(3):283–292PubMedCrossRefGoogle Scholar
  58. Jones JE, Corwin JT (1993) Replacement of lateral line sensory organs during tail regeneration in salamanders: identification of progenitor cells and analysis of leukocyte activity. J Neurosci 13(3):1022–1034PubMedGoogle Scholar
  59. Jopling C et al (2010) Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464(7288):606–609PubMedPubMedCentralCrossRefGoogle Scholar
  60. Jorgensen JM, Flock A (1976) Non-innervated sense organs of the lateral line: development in the regenerating tail of the salamander Ambystoma mexicanum. J Neurocytol 5(1):33–41PubMedCrossRefGoogle Scholar
  61. Jørgensen JM, Flock Å (1976) Non-innervated sense organs of the lateral line: development in the regenerating tail of the salamanderAmbystoma mexicanum. J Neurocytol 5(1):33–41PubMedCrossRefGoogle Scholar
  62. Kamrin AA, Singer M (1959) The growth influence of spinal ganglia implanted into the denervated forelimb regenerate of the newt. Triturus J Morphol 104:415–439PubMedCrossRefGoogle Scholar
  63. Keeble S, Maden M (1989) The relationship among retinoid structure, affinity for retinoic acid-binding protein, and ability to respecify pattern in the regenerating axolotl limb. Dev Biol 132(1):26–34PubMedCrossRefGoogle Scholar
  64. Keefe JR (1973) An analysis of urodelian retinal regeneration: I. Studies of the cellular source of retinal regeneration in Notophthalmus viridescens utilizing 3H-thymidine and colchicine. J Exp Zool 184(2):185–206PubMedCrossRefGoogle Scholar
  65. Khattak S et al (2013) Foamy virus for efficient gene transfer in regeneration studies. BMC Dev Biol 13:17PubMedPubMedCentralCrossRefGoogle Scholar
  66. Khattak S et al (2014) Optimized axolotl (Ambystoma mexicanum) husbandry, breeding, metamorphosis, transgenesis and tamoxifen-mediated recombination. Nat Protoc 9(3):529–540PubMedCrossRefGoogle Scholar
  67. Kiffmeyer WR, Tomusk EV, Mescher AL (1991) Axonal transport and release of transferrin in nerves of regenerating amphibian limbs. Dev Biol 147(2):392–402PubMedCrossRefGoogle Scholar
  68. Kikuchi K et al (2010) Primary contribution to zebrafish heart regeneration by gata4+ cardiomyocytes. Nature 464(7288):601–605PubMedPubMedCentralCrossRefGoogle Scholar
  69. King MW, Neff AW, Mescher AL (2012) The developing Xenopus limb as a model for studies on the balance between inflammation and regeneration. Anat Rec (Hoboken) 295(10):1552–1561CrossRefGoogle Scholar
  70. Kirsche K, Kirsche W (1964a) Compensatory hyperplasia and regeneration in the telencephalon of Ambystoma mexicanum after resection of a hemisphere. Z Mikrosk Anat Forsch 71:505–521PubMedGoogle Scholar
  71. Kirsche K, Kirsche W (1964b) Regenerative processes in the telencephalon of Ambystoma mexicanum. J Hirnforsch 7:421–436PubMedGoogle Scholar
  72. Knapp D et al (2013) Comparative transcriptional profiling of the axolotl limb identifies a tripartite regeneration-specific gene program. PLoS One 8(5):e61352PubMedPubMedCentralCrossRefGoogle Scholar
  73. Knopf F et al (2011) Bone regenerates via dedifferentiation of osteoblasts in the zebrafish fin. Dev Cell 20(5):713–724PubMedCrossRefGoogle Scholar
  74. Koshiba K et al (1998) Expression of Msx genes in regenerating and developing limbs of axolotl. J Exp Zool 282(6):703–714PubMedCrossRefGoogle Scholar
  75. Kragl M et al (2009) Cells keep a memory of their tissue origin during axolotl limb regeneration. Nature 460(7251):60–65PubMedCrossRefGoogle Scholar
  76. Kumar A, Brockes JP (2012) Nerve dependence in tissue, organ, and appendage regeneration. Trends Neurosci 35(11):691–699PubMedCrossRefGoogle Scholar
  77. Kumar A et al (2007) Molecular basis for the nerve dependence of limb regeneration in an adult vertebrate. Science (New York, N.Y.) 318(5851):772–777Google Scholar
  78. Lehoczky JA, Robert B, Tabin CJ (2011) Mouse digit tip regeneration is mediated by fate-restricted progenitor cells. Proc Natl Acad Sci U S A 108(51):20609–20614PubMedPubMedCentralCrossRefGoogle Scholar
  79. Lévesque M et al (2007) Transforming growth factor: β signaling is essential for limb regeneration in Axolotls. PLoS One 2(11):e1227PubMedPubMedCentralCrossRefGoogle Scholar
  80. Levesque M, Villiard E, Roy S (2010) Skin wound healing in axolotls: a scarless process. J Exp Zool B Mol Dev Evol 314(8):684–697PubMedCrossRefGoogle Scholar
  81. Li WJ et al (2006) Expression of matrix metalloproteinases and their inhibitors in fetal skin and their biological significance. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 18(5):303–306PubMedGoogle Scholar
  82. Li L et al (2012) Live imaging reveals differing roles of macrophages and neutrophils during zebrafish tail fin regeneration. J Biol Chem 287(30):25353–25360PubMedPubMedCentralCrossRefGoogle Scholar
  83. Liversage RA, McLaughlin DS (1983) Effects of delayed amputation on denervated forelimbs of adult newt. J Embryol Exp Morphol 75:1–10PubMedGoogle Scholar
  84. Lopez D, Scott EW (2015) Generation of axolotl hematopoietic chimeras. J Biol Methods 2:10CrossRefGoogle Scholar
  85. Lopez D et al (2014) Mapping hematopoiesis in a fully regenerative vertebrate: the axolotl. Blood 124(8):1232–1241PubMedPubMedCentralCrossRefGoogle Scholar
  86. Loyd RM, Tassava RA (1980) DNA synthesis and mitosis in adult newt limbs following amputation and insertion into the body cavity. J Exp Zool 214(1):61–69PubMedCrossRefGoogle Scholar
  87. Macdonald-Obermann JL, Pike LJ (2014) Different epidermal growth factor (EGF) receptor ligands show distinct kinetics and biased or partial agonism for homodimer and heterodimer formation. J Biol Chem 289(38):26178–26188PubMedPubMedCentralCrossRefGoogle Scholar
  88. Maden M (1978) Neurotrophic control of the cell cycle during amphibian limb regeneration. J Embryol Exp Morphol 48:169–175PubMedGoogle Scholar
  89. Maden M, Keeble S (1987) The role of cartilage and fibronectin during respecification of pattern induced in the regenerating amphibian limb by retinoic acid. Differentiation 36(3):175–184PubMedCrossRefGoogle Scholar
  90. Maden M, Manwell LA, Ormerod BK (2013) Proliferation zones in the axolotl brain and regeneration of the telencephalon. Neural Dev 8(1):1PubMedPubMedCentralCrossRefGoogle Scholar
  91. Mahmoud AI et al (2013) Meis1 regulates postnatal cardiomyocyte cell cycle arrest. Nature 497(7448):249–253PubMedPubMedCentralCrossRefGoogle Scholar
  92. Mariani FV (2010) Proximal to distal patterning during limb development and regeneration: a review of converging disciplines. Regen Med 5(3):451–462PubMedCrossRefGoogle Scholar
  93. Martin P (1997) Wound healing – aiming for perfect skin regeneration. Science 276(5309):75–81PubMedCrossRefGoogle Scholar
  94. Martin P et al (1993) Rapid induction and clearance of TGF beta 1 is an early response to wounding in the mouse embryo. Dev Genet 14(3):225–238PubMedCrossRefGoogle Scholar
  95. McCusker CD, Gardiner DM (2013) Positional information is reprogrammed in blastema cells of the regenerating limb of the axolotl (Ambystoma mexicanum). PLoS One 8(9):e77064PubMedPubMedCentralCrossRefGoogle Scholar
  96. McCusker CD, Gardiner DM (2014) Understanding positional cues in salamander limb regeneration: implications for optimizing cell-based regenerative therapies. Dis Model Mech 7(6):593–599PubMedPubMedCentralCrossRefGoogle Scholar
  97. McCusker C, Bryant SV, Gardiner DM (2015) The axolotl limb blastema: cellular and molecular mechanisms driving blastema formation and limb regeneration in tetrapods. Regeneration 2(2):54–71CrossRefGoogle Scholar
  98. McHedlishvili L et al (2007) A clonal analysis of neural progenitors during axolotl spinal cord regeneration reveals evidence for both spatially restricted and multipotent progenitors. Development (Cambridge, England) 134(11):2083–2093Google Scholar
  99. McHedlishvili L et al (2012) Reconstitution of the central and peripheral nervous system during salamander tail regeneration. Proc Natl Acad Sci U S A 109(34):E2258–E2266Google Scholar
  100. Menger B et al (2011) AmbLOXe – an epidermal lipoxygenase of the Mexican axolotl in the context of amphibian regeneration and its impact on human wound closure in vitro. Ann Surg 253(2):410–418PubMedCrossRefGoogle Scholar
  101. Mercader N, Tanaka EM, Torres M (2005) Proximodistal identity during vertebrate limb regeneration is regulated by Meis homeodomain proteins. Development (Cambridge, England) 132(18):4131–4142Google Scholar
  102. Mercer SE, Odelberg SJ, Simon HG (2013) A dynamic spatiotemporal extracellular matrix facilitates epicardial-mediated vertebrate heart regeneration. Dev Biol 382(2):457–469PubMedPubMedCentralCrossRefGoogle Scholar
  103. Mescher AL, Neff AW (2005) Regenerative capacity and the developing immune system. Adv Biochem Eng Biotechnol 93:39–66PubMedGoogle Scholar
  104. Mescher AL et al (1997) Transferrin is necessary and sufficient for the neural effect on growth in amphibian limb regeneration blastemas. Develop Growth Differ 39(6):677–684CrossRefGoogle Scholar
  105. Minelli G, Del Grande P (1974) Localization and quantitative analysis of the elements leading to the regeneration of the optic tectum in the adult Triturus cristatus carnifex. Z Mikrosk Anat Forsch 88(2):209–224PubMedGoogle Scholar
  106. Monaghan JR, Maden M (2012a) Visualization of retinoic acid signaling in transgenic axolotls during limb development and regeneration. Dev Biol 368(1):63–75PubMedPubMedCentralCrossRefGoogle Scholar
  107. Monaghan JR, Maden M (2012b) Cellular plasticity during vertebrate appendage regeneration. Curr Top Microbiol Immunol 367:53–74Google Scholar
  108. Monaghan JR et al (2007) Early gene expression during natural spinal cord regeneration in the salamander Ambystoma mexicanum. J Neurochem 101(1):27–40PubMedCrossRefGoogle Scholar
  109. Monaghan JR et al (2009) Microarray and cDNA sequence analysis of transcription during nerve-dependent limb regeneration. BMC Biol 7Google Scholar
  110. Monaghan JR et al (2012) Gene expression patterns specific to the regenerating limb of the Mexican axolotl. Biol Open 1(10):937–948Google Scholar
  111. Moreau-Fauvarque C et al (2003) The transmembrane semaphorin Sema4D/CD100, an inhibitor of axonal growth, is expressed on oligodendrocytes and upregulated after CNS lesion. J Neurosci 23(27):9229–9239PubMedGoogle Scholar
  112. Muneoka K, Fox WF, Bryant SV (1986) Cellular contribution from dermis and cartilage to the regenerating limb blastema in axolotls. Dev Biol 116(1):256–260PubMedCrossRefGoogle Scholar
  113. Nacu E et al (2009) Axolotl (Ambystoma mexicanum) embryonic transplantation methods. Cold Spring Harbor Protoc 2009(8):pdb-prot5265Google Scholar
  114. Nag AC, Healy CJ, Cheng M (1979) DNA synthesis and mitosis in adult amphibian cardiac muscle cells in vitro. Science 205(4412):1281–1282PubMedCrossRefGoogle Scholar
  115. Namazi MR, Fallahzadeh MK, Schwartz RA (2011) Strategies for prevention of scars: what can we learn from fetal skin? Int J Dermatol 50(1):85–93PubMedCrossRefGoogle Scholar
  116. Nardi JB, Stocum DL (1984) Surface properties of regenerating limb cells: evidence for gradation along the proximodistal axis. Differentiation 25(1–3):27–31CrossRefGoogle Scholar
  117. Niazi IA, Pescitelli MJ, Stocum DL (1985) Stage-dependent effects of retinoic acid on regenerating urodele limbs Wilhelm. Rouxs Arch Dev Biol 194(6):355–363CrossRefGoogle Scholar
  118. O’Hara CM, Chernoff EA (1994) Growth factor modulation of injury-reactive ependymal cell proliferation and migration. Tissue Cell 26(4):599–611PubMedCrossRefGoogle Scholar
  119. O’Steen WK (1958) Regeneration of the intestine in adult urodeles. J Morphol 103(3):435–477CrossRefGoogle Scholar
  120. O’Steen WK, Walker BE (1962) Radioautographic studies of regeneration in the common newt III. Regeneration and repair of the intestine. Anat Rec 142(2):179–187PubMedCrossRefGoogle Scholar
  121. Oberpriller JO, Oberpriller JC (1974) Response of the adult newt ventricle to injury. J Exp Zool 187(2):249–253PubMedCrossRefGoogle Scholar
  122. Page RB et al (2009) A model of transcriptional and morphological changes during thyroid hormone-induced metamorphosis of the axolotl. Gen Comp Endocrinol 162(2):219–232PubMedPubMedCentralCrossRefGoogle Scholar
  123. Parish CL et al (2007) Midbrain dopaminergic neurogenesis and behavioural recovery in a salamander lesion-induced regeneration model. Development 134(15):2881–2887PubMedCrossRefGoogle Scholar
  124. Piatt J (1955) Regeneration of the spinal cord in the salamander. J Exp Zool 129(1):177–207CrossRefGoogle Scholar
  125. Pinto AR, Godwin JW, Rosenthal NA (2014) Macrophages in cardiac homeostasis, injury responses and progenitor cell mobilisation. Stem Cell Res 13(3 Pt B):705–714PubMedCrossRefGoogle Scholar
  126. Porrello ER et al (2011) Transient regenerative potential of the neonatal mouse heart. Science 331(6020):1078–1080PubMedPubMedCentralCrossRefGoogle Scholar
  127. Porrello ER et al (2013) Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. Proc Natl Acad Sci U S A 110(1):187–192PubMedPubMedCentralCrossRefGoogle Scholar
  128. Poss KD, Wilson LG, Keating MT (2002) Heart regeneration in zebrafish. Science 298(5601):2188–2190PubMedCrossRefGoogle Scholar
  129. Powell JA (1969) Analysis of histogenesis and regenerative ability of denervated forelimb regenerates of Triturus viridescens. J Exp Zool 170(2):125–147PubMedCrossRefGoogle Scholar
  130. Rao N et al (2009) Proteomic analysis of blastema formation in regenerating axolotl limbs. BMC Biol 7:83PubMedPubMedCentralCrossRefGoogle Scholar
  131. Reginelli AD et al (1995) Digit tip regeneration correlates with regions of Msx1 (Hox 7) expression in fetal and newborn mice. Development 121(4):1065–1076PubMedGoogle Scholar
  132. Richter W (1968) Regenerative processes following removal of the caudal sector of the telencephalon including the telencephalo-diencephalic border region in Ambystoma mexicanum (In German). J Hirnforsch 10(6):515–534PubMedGoogle Scholar
  133. Richter W, Kranz D (1981) Autoradiographic investigations on postnatal proliferative activity of the telencephalic and diencephalic matrix-zones in the axolotl (Ambystoma mexicanum), with special references to the olfactory organ (author’s transl). Z Mikrosk Anat Forsch 95(6):883–904PubMedGoogle Scholar
  134. Rinkevich Y et al (2014) Clonal analysis reveals nerve-dependent and independent roles on mammalian hind limb tissue maintenance and regeneration. Proc Natl Acad Sci U S A 111(27):9846–9851PubMedPubMedCentralCrossRefGoogle Scholar
  135. Rumyantsev PP (1966) Autoradiographic study on the synthesis of DNA, RNA, and proteins in normal cardiac muscle cells and those changed by experimental injury. Folia Histochem Cytochem (Krakow) 4(4):397–424Google Scholar
  136. Sallin P et al (2015) A dual epimorphic and compensatory mode of heart regeneration in zebrafish. Dev Biol 399(1):27–40PubMedCrossRefGoogle Scholar
  137. Sandoval-Guzman T et al (2014) Fundamental differences in dedifferentiation and stem cell recruitment during skeletal muscle regeneration in two salamander species. Cell Stem Cell 14(2):174–187PubMedCrossRefGoogle Scholar
  138. Satoh A et al (2011) Blastema induction in aneurogenic state and Prrx-1 regulation by MMPs and FGFs in Ambystoma mexicanum limb regeneration. Dev Biol 355(2):263–274PubMedCrossRefGoogle Scholar
  139. Scadding SR, Liversage RA (1974) Studies on the response of the adult newt kidney to partial nephrectomy. Am J Anat 140(3):349–367PubMedCrossRefGoogle Scholar
  140. Scadding SR, Maden M (1994) Retinoic acid gradients during limb regeneration. Dev Biol 162(2):608–617PubMedCrossRefGoogle Scholar
  141. Schnapp E et al (2005) Hedgehog signaling controls dorsoventral patterning, blastema cell proliferation and cartilage induction during axolotl tail regeneration. Development (Cambridge, England) 132(14):3243–3253Google Scholar
  142. Schotté OE, Butler EG (1944) Phases in regeneration of the urodele limb and their dependence upon the nervous system. J Exp Zool 97(2):95–121CrossRefGoogle Scholar
  143. Seifert AW, Maden M (2014) New insights into vertebrate skin regeneration. Int Rev Cell Mol Biol 310:129–169PubMedCrossRefGoogle Scholar
  144. Seifert AW et al (2012) Skin regeneration in adult axolotls: a blueprint for scar-free healing in vertebrates. PloS One 7(4):e32875PubMedPubMedCentralCrossRefGoogle Scholar
  145. Shypitsyna A et al (2011) Origin of Nogo-A by domain shuffling in an early jawed vertebrate. Mol Biol Evol 28(4):1363–1370PubMedCrossRefGoogle Scholar
  146. Singer M (1952) The influence of the nerve in regeneration of the amphibian extremity. Q Rev Biol 27(2):169–200PubMedCrossRefGoogle Scholar
  147. Singer M (1964) The trophic quality of the neuron: some theoretical considerations. Prog Brain Res 13:228–232PubMedCrossRefGoogle Scholar
  148. Singer M, Craven L (1948) The growth and morphogenesis of the regenerating forelimb of adult Triturus following denervation at various stages of development. J Exp Zool 108(2):279–308PubMedCrossRefGoogle Scholar
  149. Sirbulescu RF, Zupanc GK (2009) Dynamics of caspase-3-mediated apoptosis during spinal cord regeneration in the teleost fish, Apteronotus leptorhynchus. Brain Res 1304:14–25PubMedCrossRefGoogle Scholar
  150. Smith JJ et al (2005a) A comprehensive expressed sequence tag linkage map for tiger salamander and Mexican axolotl: enabling gene mapping and comparative genomics in ambystoma. Genetics 171(3):1161–1171PubMedPubMedCentralCrossRefGoogle Scholar
  151. Smith JJ et al (2005b) Sal-site: integrating new and existing ambystomatid salamander research and informational resources. BMC Genomics 6:181PubMedPubMedCentralCrossRefGoogle Scholar
  152. Smith JJ et al (2009) Genic regions of a large salamander genome contain long introns and novel genes. BMC Genomics 10:19PubMedPubMedCentralCrossRefGoogle Scholar
  153. Sobkow L et al (2006) A germline GFP transgenic axolotl and its use to track cell fate: dual origin of the fin mesenchyme during development and the fate of blood cells during regeneration. Dev Biol 290(2):386–397PubMedCrossRefGoogle Scholar
  154. Sousa S et al (2011) Differentiated skeletal cells contribute to blastema formation during zebrafish fin regeneration. Development (Cambridge, England) 138(18):3897–3905Google Scholar
  155. Spalding KL et al (2005) Retrospective birth dating of cells in humans. Cell 122(1):133–143PubMedCrossRefGoogle Scholar
  156. Spallanzani L (1769) An essay on animal reproductions (Translated from the Italian, 1768, by M. Maty).T. Becket, LondonGoogle Scholar
  157. Stewart R et al (2013) Comparative RNA-seq analysis in the unsequenced axolotl: the oncogene burst highlights early gene expression in the blastema. PLoS Comput Biol 9(3):e1002936PubMedPubMedCentralCrossRefGoogle Scholar
  158. Stocum DL, Cameron JA (2011) Looking proximally and distally: 100 years of limb regeneration and beyond. Dev Dyn: An Off Publ Am Assoc Anat 240(5):943–968CrossRefGoogle Scholar
  159. Stone LS (1933) The development of lateral-line sense organs in amphibians observed in living and vital-stained preparations. J Comp Neurol 57(3):507–540CrossRefGoogle Scholar
  160. Stone LS (1937) Further experimental studies of the development of lateral-line sense organs in amphibians observed in living preparations. J Comp Neurol 68(1):83–115CrossRefGoogle Scholar
  161. Stone LS (1950) Neural retina degeneration followed by regeneration from surviving retinal pigment cells in grafted adult salamander eyes. Anat Rec 106(1):89–109PubMedCrossRefGoogle Scholar
  162. Suetsugu-Maki R et al (2012) Lens regeneration in axolotl: new evidence of developmental plasticity. BMC Biol 10:103PubMedPubMedCentralCrossRefGoogle Scholar
  163. Tanaka EM, Ferretti P (2009) Considering the evolution of regeneration in the central nervous system. Nat Rev Neurosci 10(10):713–723PubMedCrossRefGoogle Scholar
  164. Tanaka EM et al (1997) Newt myotubes reenter the cell cycle by phosphorylation of the retinoblastoma protein. J Cell Biol 136(1):155–165PubMedPubMedCentralCrossRefGoogle Scholar
  165. Tanner K et al (2009) Coherent movement of cell layers during wound healing by image correlation spectroscopy. Biophys J 97(7):2098–2106PubMedPubMedCentralCrossRefGoogle Scholar
  166. Tassava RA, Garling DJ (1979) Regenerative responses in larval axolotl limbs with skin grafts over the amputation surface. J Exp Zool 208(1):97–110PubMedCrossRefGoogle Scholar
  167. Tassava RA, Bennett LL, Zitnik GD (1974) DNA synthesis without mitosis in amputated denervated forelimbs of larval axolotls. J Exp Zool 190(1):111–116PubMedCrossRefGoogle Scholar
  168. Tate JM, Oberpriller JO, Oberpriller JC (1989) Analysis of DNA synthesis in cell cultures of the adult newt cardiac myocyte. Tissue Cell 21(3):335–342PubMedCrossRefGoogle Scholar
  169. Thornton CS (1938) The histogenesis of the regenerating fore limb of larval Amblystoma after exarticulation of the humerus. J Morphol 62(2):219–241CrossRefGoogle Scholar
  170. Thornton CS (1960) Influence of an eccentric epidermal cap on limb regeneration in Amblystoma larvae. Dev Biol 2:551–569PubMedCrossRefGoogle Scholar
  171. Todd TJ (1823) On the process of reproduction of the members of the aquatic salamander. Q J Sci Lit Arts 16:84–96Google Scholar
  172. Tomlinson BL, Tassava RA (1987) Dorsal root ganglia grafts stimulate regeneration of denervated urodele forelimbs: timing of graft implantation with respect to denervation. Development 99(2):173–186PubMedGoogle Scholar
  173. Tournefier A, Fellah S, Charlemagne J (1988) Monoclonal antibodies to axolotl immunoglobulins specific for different heavy chains isotypes expressed by independent lymphocyte subpopulations. Immunol Lett 18(2):145–148PubMedCrossRefGoogle Scholar
  174. Uchida T, Hanaoka K (1949) The occurence of oviform cells by hormonal injection in the regenerated testes of a newt. Cytologia 15:109–130CrossRefGoogle Scholar
  175. Vargas-Gonzalez A et al (2005) Myocardial regeneration in Ambystoma mexicanum after surgical injury. Arch Cardiol Mex 75(Suppl 3):S3-21-9Google Scholar
  176. Vethamany-Globus S, Liversage RA (1973) Effects of insulin insufficiency on forelimb and tail regeneration in adult Diemictylus viridescens. J Embryol Exp Morphol 30(2):427–447PubMedGoogle Scholar
  177. Voss SR, Epperlein HH, Tanaka EM (2009) Ambystoma mexicanum, the axolotl: a versatile amphibian model for regeneration, development, and evolution studies. Cold Spring Harbor Protoc 2009(8):pdb.emo128Google Scholar
  178. Voss SR et al (2015) Gene expression during the first 28 days of axolotl limb regeneration I: experimental design and global analysis of gene expression. Regeneration 2(3):120–136CrossRefGoogle Scholar
  179. Wang L, Marchionni MA, Tassava RA (2000) Cloning and neuronal expression of a type III newt neuregulin and rescue of denervated, nerve-dependent newt limb blastemas by rhGGF2. J Neurobiol 43(2):150–158PubMedCrossRefGoogle Scholar
  180. Whited JL, Lehoczky JA, Tabin CJ (2012) Inducible genetic system for the axolotl. Proc Natl Acad Sci U S A 109(34):13662–13667PubMedPubMedCentralCrossRefGoogle Scholar
  181. Whited JL et al (2013) Pseudotyped retroviruses for infecting axolotl in vivo and in vitro. Development 140(5):1137–1146PubMedPubMedCentralCrossRefGoogle Scholar
  182. Williams DD (1961) Liver Regeneration in the Newt. Triturus viridescens. Physiol Zool 34(3):256–259CrossRefGoogle Scholar
  183. Witman N et al (2011) Recapitulation of developmental cardiogenesis governs the morphological and functional regeneration of adult newt hearts following injury. Dev Biol 354(1):67–76PubMedCrossRefGoogle Scholar
  184. Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214(2):199–210PubMedPubMedCentralCrossRefGoogle Scholar
  185. Xue M, Jackson CJ (2015) Extracellular matrix reorganization during wound healing and its impact on abnormal scarring. Adv Wound Care (New Rochelle) 4(3):119–136CrossRefGoogle Scholar
  186. Yang EV, Bryant SV (1994) Developmental regulation of a matrix metalloproteinase during regeneration of axolotl appendages. Dev Biol 166(2):696–703PubMedCrossRefGoogle Scholar
  187. Yang EV et al (1999) Expression of Mmp-9 and related matrix metalloproteinase genes during axolotl limb regeneration. Dev Dyn 216(1):2–9PubMedCrossRefGoogle Scholar
  188. Yannas IV, Colt J, Wai YC (1996) Wound contraction and scar synthesis during development of the amphibian Rana catesbeiana. Wound Repair Regen 4(1):29–39PubMedCrossRefGoogle Scholar
  189. Yates CC, Hebda P, Wells A (2012) Skin wound healing and scarring: fetal wounds and regenerative restitution. Birth Defects Res C Embryo Today 96(4):325–333PubMedPubMedCentralCrossRefGoogle Scholar
  190. Yiu G, He Z (2006) Glial inhibition of CNS axon regeneration. Nat Rev Neurosci 7(8):617–627PubMedPubMedCentralCrossRefGoogle Scholar
  191. Yun MH, Davaapil H, Brockes JP (2015) Recurrent turnover of senescent cells during regeneration of a complex structure. Elife 4:e05505CrossRefGoogle Scholar
  192. Zgheib C, Xu J, Liechty KW (2014) Targeting inflammatory cytokines and extracellular matrix composition to promote wound regeneration. Adv Wound Care (New Rochelle) 3(4):344–355CrossRefGoogle Scholar
  193. Zhang P, Wake DB (2009) Higher-level salamander relationships and divergence dates inferred from complete mitochondrial genomes. Mol Phylogenet Evol 53(2):492–508PubMedCrossRefGoogle Scholar
  194. Zhang F, Ferretti P, Clarke JD (2003) Recruitment of postmitotic neurons into the regenerating spinal cord of urodeles. Dev Dyn 226(2):341–348PubMedCrossRefGoogle Scholar
  195. Zhang R et al (2013) In vivo cardiac reprogramming contributes to zebrafish heart regeneration. Nature 498(7455):497–501PubMedPubMedCentralCrossRefGoogle Scholar
  196. Zhu W et al (2012) Activation of germline-specific genes is required for limb regeneration in the Mexican axolotl. Dev Biol 370(1):42–51PubMedPubMedCentralCrossRefGoogle Scholar
  197. Ziegels J (1971) The melanocytes of the axolotl. Their modifications during skin regeneration. Arch Biol (Liege) 82(3):407–428Google Scholar
  198. Zukor KA, Kent DT, Odelberg SJ (2011) Meningeal cells and glia establish a permissive environment for axon regeneration after spinal cord injury in newts. Neural Dev 6(1):1PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Johanna E. Farkas
    • 1
  • Piril Erler
    • 1
  • Polina D. Freitas
    • 1
  • Alexandra E. Sweeney
    • 1
    • 2
  • James R. Monaghan
    • 1
    Email author
  1. 1.Department of BiologyNortheastern UniversityBostonUSA
  2. 2.School of Life Sciences, Queen’s Medical CentreNottingham UniversityNottinghamUK

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