Current Pathobiology Reports

, Volume 6, Issue 1, pp 61–69 | Cite as

Tissue Repair and Epimorphic Regeneration: an Overview

  • Ricardo Londono
  • Aaron X. Sun
  • Rocky S. Tuan
  • Thomas P. Lozito
Wound Healing and Tissue Repair (CC Yates, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Wound Healing and Tissue Repair


Purpose of the Review

This manuscript discusses wound healing as a component of epimorphic regeneration and the role of the immune system in this process.

Recent Findings

Epimorphic regeneration involves formation of a blastema, a mass of undifferentiated cells capable of giving rise to the regenerated tissues. The apical epithelial cap plays an important role in blastemal formation.


True regeneration is rarely observed in mammals. With the exception of transgenic strains, tissue repair in mammals usually leads to non-functional fibrotic tissue formation. In contrast, a number of lower order species including planarians, salamanders, and reptiles have the ability to overcome the burden of scarring and tissue loss through complex adaptations that allow them to regenerate various anatomic structures through epimorphic regeneration. Blastemal cells have been suggested to originate via various mechanisms including dedifferentiation, transdifferentiation, migration of pre-existing adult stem cell niches, and combinations of these.


Wound healing Super-healing organisms Blastema Regeneration Regenerative medicine Epimorphic regeneration 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Michalopoulos G, Cianciulli HD, Novotny AR, Kligerman AD, Strom SC, Jirtle RL. Liver regeneration studies with rat hepatocytes in primary culture. Cancer Res. 1982;42(11):4673–82. PubMedGoogle Scholar
  2. 2.
    Steinberg B. Bone marrow regeneration in experimental benzene intoxication. Blood. 1949;4(5):550–6. PubMedGoogle Scholar
  3. 3.
    Barker N. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nat Rev Mol Cell Biol. 2014;15(1):19–33. Scholar
  4. 4.
    Mimeault M, Hauke R, Batra SK. Stem cells: a revolution in therapeutics—recent advances in stem cell biology and their therapeutic applications in regenerative medicine and cancer therapies. Clin Pharmacol Ther. 2007;82(3):252–64. Scholar
  5. 5.
    Broughton G, Janis JE, Attinger CE. The basic science of wound healing. Plast Reconstr Surg. 2006;117(7 Suppl):12S–34S. Scholar
  6. 6.
    Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation. 1990;81(4):1161–72. CrossRefPubMedGoogle Scholar
  7. 7.
    Marsell R, Einhorn TA. The biology of fracture healing. Injury. 2011;42(6):551–5. Scholar
  8. 8.
    Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology. 2006;43(2 SUPPL. 1)
  9. 9.
    Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453(7193):314–21. Scholar
  10. 10.
    Maginnis TL. The costs of autotomy and regeneration in animals: a review and framework for future research. Behav Ecol. 2006;17(5):857–72. Scholar
  11. 11.
    Xue M, Jackson CJ. Extracellular matrix reorganization during wound healing and its impact on abnormal scarring. Adv Wound Care. 2015;4(3):119–36. Scholar
  12. 12.
    Reichman DE, Greenberg JA. Reducing surgical site infections: a review. Rev Obstet Gynecol. 2009;2(4):212–21. Scholar
  13. 13.
    Hantash BM, Zhao L, Knowles JA, Lorenz HP. Adult and fetal wound healing. Front Biosci. 2008;13:51–61. Scholar
  14. 14.
    Bely AE, Nyberg KG. Evolution of animal regeneration: re-emergence of a field. Trends Ecol Evol. 2010;25(3):161–70. Scholar
  15. 15.
    Bely AE. Evolutionary loss of animal regeneration: pattern and process. Integr Comp Biol. 2010;50:515–27. Scholar
  16. 16.
    Bosch TCG. Why polyps regenerate and we don’t: towards a cellular and molecular framework for hydra regeneration. Dev Biol. 2007;303(2):421–33. Scholar
  17. 17.
    Elliott SA, Sánchez Alvarado A. The history and enduring contributions of planarians to the study of animal regeneration. Wiley Interdiscip Rev Dev Biol. 2013;2(3):301–26. Scholar
  18. 18.
    Ben Khadra Y, Ferrario C, Di Benedetto C, et al. Wound repair during arm regeneration in the red starfish Echinaster sepositus. Wound Repair Regen. 2015;23(4):611–22. Scholar
  19. 19.
    Kizil C, Kaslin J, Kroehne V, Brand M. Adult neurogenesis and brain regeneration in zebrafish. Dev Neurobiol. 2012;72(3):429–61. Scholar
  20. 20.
    Kang J, Hu J, Karra R, et al. Modulation of tissue repair by regeneration enhancer elements. Nature. 2016;532(7598):201–6. Scholar
  21. 21.
    •• Sandoval-Guzmán T, Wang H, Khattak S, et al. Fundamental differences in dedifferentiation and stem cell recruitment during skeletal muscle regeneration in two salamander species. Cell Stem Cell. 2014;14(2):174–87. This study is important because it highlights different blastema formation mechanims in closely related species. CrossRefPubMedGoogle Scholar
  22. 22.
    Kragl M, Knapp D, Nacu E, et al. Cells keep a memory of their tissue origin during axolotl limb regeneration. Nature. 2009;460(7251):60–5. Scholar
  23. 23.
    Tsonis PA, Madhavan M, Tancous EE, Del Rio-Tsonis K. A newt’s eye view of lens regeneration. Int J Dev Biol. 2004;48(8–9):975–80. Scholar
  24. 24.
    Maden M, Manwell LA, Ormerod BK. Proliferation zones in the axolotl brain and regeneration of the telencephalon. Neural Dev. 2013;8:1. Scholar
  25. 25.
    Berg DA, Kirkham M, Beljajeva A, et al. Efficient regeneration by activation of neurogenesis in homeostatically quiescent regions of the adult vertebrate brain. Development. 2010;137(24):4127–34. Scholar
  26. 26.
    Parish CL, Beljajeva A, Arenas E, Simon A. Midbrain dopaminergic neurogenesis and behavioural recovery in a salamander lesion-induced regeneration model. Development. 2007;134(15):2881–7. Scholar
  27. 27.
    • Godwin JW, Debuque R, Salimova E, Rosenthal NA. Heart regeneration in the salamander relies on macrophage-mediated control of fibroblast activation and the extracellular landscape. NPJ Regen Med. 2017;2(1):22. This study is important because it highlights the importance of the immune system in epimorphic regeneration. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Lozito TP, Tuan RS. Lizard tail regeneration: regulation of two distinct cartilage regions by Indian hedgehog. Dev Biol. 2015;399(2):249–62. Scholar
  29. 29.
    Lozito TP, Tuan RS, Alibardi L, et al. Lizard tail skeletal regeneration combines aspects of fracture healing and blastema-based regeneration. Development. 2016;143(16):2946–57. Scholar
  30. 30.
    Reddien PW, Alvarado AS. Fundamentals of planarian regeneration. Annu Rev Cell Dev Biol. 2004;20(1):725–57. Scholar
  31. 31.
    Stone JS, Cotanche DA. Hair cell regeneration in the avian auditory epithelium. Int J Dev Biol. 2007;51(6–7):633–47. Scholar
  32. 32.
    Clark LD, Clark RK, Heber-Katz E. A new murine model for mammalian wound repair and regeneration. Clin Immunol Immunopathol. 1998;88(1):35–45. Scholar
  33. 33.
    Seifert AW, Kiama SG, Seifert MG, Goheen JR, Palmer TM, Maden M. Skin shedding and tissue regeneration in African spiny mice (Acomys). Nature. 2012;489(7417):561–5. Scholar
  34. 34.
    Bedelbaeva K, Snyder A, Gourevitch D, et al. Lack of p21 expression links cell cycle control and appendage regeneration in mice. Proc Natl Acad Sci U S A. 2010;107(13):5845–50. Scholar
  35. 35.
    Shyh-Chang N, Zhu H, Yvanka de Soysa T, et al. Lin28 enhances tissue repair by reprogramming cellular metabolism. Cell. 2013;155(4):778–92. Scholar
  36. 36.
    Goss RJ, Grimes LN. Epidermal downgrowths in regenerating rabbit ear holes. J Morphol. 1975;146(4):533–42. Scholar
  37. 37.
    Javanmard AOS, Bahrami AR, Mahmoodi Z, Saeinasab M, Mahdavi SHahri N, Moghaddam MM. Studying the expression patterns of OCT4 and SOX2. Proteins in regenerating rabbit ear tissue. World Rabbit Sci. 2016;24(1):155–64.CrossRefGoogle Scholar
  38. 38.
    Price J, Faucheux C, Allen S. Deer antlers as a model of mammalian regeneration. Curr Top Dev Biol. 2005;67:1–48. Scholar
  39. 39.
    Godwin J. The promise of perfect adult tissue repair and regeneration in mammals: learning from regenerative amphibians and fish. BioEssays. 2014;36(9):861–71. Scholar
  40. 40.
    Mescher AL, Neff AW, King MW. Changes in the inflammatory response to injury and its resolution during the loss of regenerative capacity in developing Xenopus limbs. PLoS One. 2013;8(11)
  41. 41.
    Morgan TH. Regeneration. New York: Macmillan; 1901.CrossRefGoogle Scholar
  42. 42.
    Agata K, Saito Y, Nakajima E. Unifying principles of regeneration I: epimorphosis versus morphallaxis. Develop Growth Differ. 2007;49(2):73–8. Scholar
  43. 43.
    • Simkin J, Sammarco MC, Dawson LA, Schanes PP, Yu L, Muneoka K. The mammalian blastema: regeneration at our fingertips. Regeneration. 2015:93–105. This study highlights blastema formation in mammals.
  44. 44.
    Gilbert EAB, Delorme SL, Vickaryous MK. The regeneration blastema of lizards: an amniote model for the study of appendage replacement. Regeneration. 2015;2(2):45–53. Scholar
  45. 45.
    McCusker C, Bryant SV, Gardiner DM. The axolotl limb blastema: cellular and molecular mechanisms driving blastema formation and limb regeneration in tetrapods. Regeneration. 2015;2(2):54–71. Scholar
  46. 46.
    Kikuchi K, Holdway JE, Werdich AA, et al. Primary contribution to zebrafish heart regeneration by gata4+ cardiomyocytes. Nature. 2010;464(7288):601–5. Scholar
  47. 47.
    Jopling C, Sleep E, Raya M, Martí M, Raya A, Belmonte JCI. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature. 2010;464(7288):606–9. Scholar
  48. 48.
    Lozito TP, Tuan RS. Lizard tail regeneration as an instructive model of enhanced healing capabilities in an adult amniote. Connect Tissue Res. 2017;58(2):145–54. Scholar
  49. 49.
    Seifert A, Monaghan J, Voss R, Maden M. Skin regeneration in adult axolotls: a blueprint for scar-free healing in vertebrates. PLoS One. 2012;7(4)
  50. 50.
    Breedis C. Regeneration of hair follicles and sebaceous glands from the epithelium of scars in the rabbit. Cancer Res. 1954;14(8):575–9.PubMedGoogle Scholar
  51. 51.
    Ito M, Yang Z, Andl T, et al. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature. 2007;447(7142):316–20. Scholar
  52. 52.
    Dang CM, Beanes SR, Lee H, Zhang X, Soo C, Ting K. Scarless fetal wounds are associated with an increased matrix metalloproteinase-to-tissue-derived inhibitor of metalloproteinase ratio. Plast Reconstr Surg. 2003;111(7):2273–85. Scholar
  53. 53.
    Soo C, Shaw WW, Zhang X, Longaker MT, Howard EW, Ting K. Differential expression of matrix metalloproteinases and their tissue-derived inhibitors in cutaneous wound repair. Plast Reconstr Surg. 2000;105(2):638–47.; CrossRefPubMedGoogle Scholar
  54. 54.
    Cox PG. Some aspects of tail regeneration in the lizard, Anolis carolinensis. I. A description based on histology and autoradiography. J Exp Zool. 1969;171(2):127–49. Scholar
  55. 55.
    McLean KE, Vickaryous MK. A novel amniote model of epimorphic regeneration: the leopard gecko. BMC Dev Biol. 2011;11(1):50. Scholar
  56. 56.
    Salpeter MM, Singer M. Differentiation of the submicroscopic adepidermal membrane during limb regeneration in adult Triturus, including a note on the use of the term basement membrane. Anat Rec. 1960;136:27–39.CrossRefPubMedGoogle Scholar
  57. 57.
    Tassava RA, Johnson-Wint B, Gross J. Regenerate epithelium and skin glands of the adult newt react to the same monoclonal antibody. J Exp Zool. 1986;239(2):229–40. Scholar
  58. 58.
    Goldhamer DJ, Tomlinson BL, Tassava RA. A developmentally regulated wound epithelial antigen of the newt limb regenerate is also present in a variety of secretory/transport cell types. Dev Biol. 1989;135(2):392–404.CrossRefPubMedGoogle Scholar
  59. 59.
    Thornton CS. Influence of an eccentric epidermal cap on limb regeneration in Amblystoma larvae. Dev Biol. 1960;2(6):551–69. Scholar
  60. 60.
    Brockes JP. Amphibian limb regeneration: rebuilding a complex structure. Science (80-). 1997;276(5309):81–7. Scholar
  61. 61.
    Christensen RN, Tassava RA. Apical epithelial cap morphology and fibronectin gene expression in regenerating axolotl limbs. Dev Dyn. 2000;217(2):216–24.<216::AID-DVDY8>3.0.CO;2-8.CrossRefPubMedGoogle Scholar
  62. 62.
    Satoh A, Bryant SV, Gardiner DM. Nerve signaling regulates basal keratinocyte proliferation in the blastema apical epithelial cap in the axolotl (Ambystoma mexicanum). Dev Biol. 2012;366(2):374–81. Scholar
  63. 63.
    Onda H, Tassava RA. Expression of the 9G1 antigen in the apical cap of axolotl regenerates requires nerves and mesenchyme. J Exp Zool. 1991;257(3):336–49. Scholar
  64. 64.
    Stocum DL, Dearlove GE. Epidermal-mesodermal interaction during morphogenesis of the limb regeneration blastema in larval salamanders. J Exp Zool. 1972;181(1):49–61. Scholar
  65. 65.
    Endo T, Bryant SV, Gardiner DM. A stepwise model system for limb regeneration. Dev Biol. 2004;270(1):135–45. Scholar
  66. 66.
    Singer M. The influence of the nerve in regeneration of the amphibian extremity. Q Rev Biol. 1952;27(2):169–200.CrossRefPubMedGoogle Scholar
  67. 67.
    Kumar A, Godwin JW, Gates PB, Garza-Garcia AA, Brockes JP. Molecular basis for the nerve dependence of limb regeneration in an adult vertebrate. Science. 2007;318(5851):772–7. Scholar
  68. 68.
    Singer M, Rzehak K, Maier CS. The relation between the caliber of the axon and the trophic activity of nerves in limb regeneration. J Exp Zool. 1967;166(1):89–97. Scholar
  69. 69.
    Bryant SV, French V, Bryant PJ. Distal regeneration and symmetry. Science. 1981;212(4498):993–1002. Scholar
  70. 70.
    French V, Bryant PJ, Bryant SV. Pattern regulation in epimorphic fields. Science. 1976;193(4257):969–81. Scholar
  71. 71.
    Woodland WNF. Memoirs: some observations on caudal autotomy and regeneration in the gecko (Hemidactylus flaviviridis, Rppel), with notes on the tails of Sphenodon and Pygopus. Q J Microsc Sci. 1920;s2–65(257):63–100. Google Scholar
  72. 72.
    Bellairs AD, Bryant SV: Autotomy and regeneration in reptiles (Development B). In The Biology Of The Reptilia, Volume 15 Edited by: Gans C, Billet F. New York: John Wiley & Sons, Inc. 1985;303-410.Google Scholar
  73. 73.
    Werner YL. Regeneration of the caudal axial skeleton in a gekkonid lizard ( Hemidactylus ) with particular reference to the ‘latent’ period. Acta Zool. 1967;48(1–2):103–25. Scholar
  74. 74.
    Delorme SL, Lungu IM, Vickaryous MK. Scar-free wound healing and regeneration following tail loss in the leopard gecko, Eublepharis macularius. Anat Rec Adv Integr Anat Evol Biol. 2012;295(10):1575–95. Scholar
  75. 75.
    Gourevitch DL, Clark L, Bedelbaeva K, Leferovich J, Heber-Katz E. Dynamic changes after murine digit amputation: the MRL mouse digit shows waves of tissue remodeling, growth, and apoptosis. Wound Repair Regen. 2009;17(3):447–55. Scholar
  76. 76.
    Fernando WA, Leininger E, Simkin J, et al. Wound healing and blastema formation in regenerating digit tips of adult mice. Dev Biol. 2011;350(2):301–10. Scholar
  77. 77.
    Slack JMW. Amphibian muscle regeneration - dedifferentiation or satellite cells? Trends Cell Biol. 2006;16(6):273–5. Scholar
  78. 78.
    Nye HLD, Cameron JA, Chernoff EAG, Stocum DL. Regeneration of the urodele limb: a review. Dev Dyn. 2003;226(2):280–94. Scholar
  79. 79.
    Jopling C, Boue S, Belmonte JCI. Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration. Nat Rev Mol Cell Biol. 2011;12(2):79–89. Scholar
  80. 80.
    Hay ED. Electron microscopic observations of muscle dedifferentiation in regenerating Amblystoma limbs. Dev Biol. 1959;1(6):555–85. Scholar
  81. 81.
    Namenwirth M. The inheritance of cell differentiation during limb regeneration in the axolotl. Dev Biol. 1974;41(1):42–56. Scholar
  82. 82.
    Chen Z-L, Yu W-M, Strickland S. Peripheral regeneration. Annu Rev Neurosci. 2007;30(1):209–33. Scholar
  83. 83.
    Mirsky R, Woodhoo A, Parkinson DB, Arthur-Farraj P, Bhaskaran A, Jessen KR. Novel signals controlling embryonic Schwann cell development, myelination and dedifferentiation. J Peripher Nerv Syst. 2008;13:122–35. CrossRefPubMedGoogle Scholar
  84. 84.
    Tanaka EM, Gann AAF, Gates PB, Brockes JP. Newt myotubes reenter the cell cycle by phosphorylation of the retinoblastoma protein. J Cell Biol. 1997;136(1):155–65. Scholar
  85. 85.
    Thitoff AR, Call MK, Del Rio-Tsonis K, Tsonis PA. Unique expression patterns of the retinoblastoma (Rb) gene in intact and lens regeneration-undergoing newt eyes. Anat Rec A Discov Mol Cell Evol Biol. 2003;271(August 2002):185–8. Scholar
  86. 86.
    Maki N, Martinson J, Nishimura O, et al. Expression profiles during dedifferentiation in newt lens regeneration revealed by expressed sequence tags. Mol Vis. 2010;16:72–8.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Kahn EB, Simpson SB. Satellite cells in mature, uninjured skeletal muscle of the lizard tail. Dev Biol. 1974;37(1):219–23. Scholar
  88. 88.
    Alibardi L. Immunolocalization of Nestin in the lizard Podarcis muralis indicates up-regulation during the process of tail regeneration and epidermal differentiation. Ann Anat - Anat Anzeiger. 2014;196(2–3):135–43. Scholar
  89. 89.
    Zhou Y, Xu Q, Li D, et al. Early neurogenesis during caudal spinal cord regeneration in adult Gekko japonicus. J Mol Histol. 2013;44(3):291–7. Scholar
  90. 90.
    Anton HJ. The origin of blastema cells and protein synthesis during forelimb regeneration in Triturus. In Regeneration in Animals Edited by: Kiortsis V, Trampusch HAL. Amsterdam: North-Holland Pub Co. 1965;377-395.Google Scholar
  91. 91.
    Burgess AMC. The developmental potentialities of regeneration blastema cell nuclei as determined by nuclear transplantation. J Embryol Exp Morpholog. 1967;18(1):27–41. Google Scholar
  92. 92.
    Zanier E, Bordoni B. A multidisciplinary approach to scars: a narrative review. J Multidiscip Healthc. 2015;8:359–63. Scholar
  93. 93.
    Burlacu A. Dupuytren’s contracture: a new perspective on treatment. Maedica. 2010;5(1):67–8. PubMedPubMedCentralGoogle Scholar
  94. 94.
    Goel A, Shrivastava P. Post-burn scars and scar contractures. Indian J Plast Surg. 2010;43(Suppl):S63–71. Scholar
  95. 95.
    Rabello FB, Souza CD, Júnior JAF. Update on hypertrophic scar treatment. Clinics. 2014;69(8):565–73. Scholar
  96. 96.
    Londono R, Badylak SF. Regenerative medicine strategies for esophageal repair. Tissue Eng Part B Rev. 2015;21(4):393–410. Scholar
  97. 97.
    Cojocaru M, Cojocaru IM, Silosi I, Vrabie CD. Pulmonary manifestations of systemic autoimmune diseases. Maedica. 2011;6(3):224–9. PubMedPubMedCentralGoogle Scholar
  98. 98.
    Mescher AL, Neff AW. Regenerative capacity and the developing immune system. Adv Biochem Eng Biotechnol. 2005;93:39–66.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ricardo Londono
    • 1
  • Aaron X. Sun
    • 1
    • 2
    • 3
  • Rocky S. Tuan
    • 1
    • 3
  • Thomas P. Lozito
    • 1
  1. 1.Center for Cellular and Molecular Engineering, Department of Orthopaedic SurgeryUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.School of MedicineUniversity of PittsburghPittsburghUSA
  3. 3.Department of BioengineeringUniversity of PittsburghPittsburghUSA

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