Regeneration of Mammalian Skin


Regeneration and repair of tissue injury in mammalian skin is an intricate process in which cellular, biochemical and molecular interactions occur. These interactions are the foundations of new therapeutics and approaches designed to facilitate tissue repair. The ultimate goal is to regenerate skin such that the complete structural and functional properties of the wounded area are restored to the levels before injury without a scar. Novel pharmaceutical approaches to scar reduction are under development, with the furthest progressed being avotermin (Juvista; transforming growth factor beta 3 (TGFβ3)). In addition, new synthetic biomaterials are constantly being developed that may in future enable some control over the capacity for tissues to regenerate by manipulating stem cells, cell adhesion, growth and differentiation for optimal tissue development. The success of these new approaches to skin regeneration is likely to be underpinned by the manipulation of the mechanisms responsible for wound repair and regeneration.

Key Concepts:

  • Like other animals such as newts and salamanders, mammals have the ability to regenerate tissues.

  • Many wound signals probably control more than one cell activity, and regeneration probably constitutes an orchestrated response to a mixture of such signals.

  • The processes involved during wound healing can trigger an embryonic state in the skin which makes it receptive to regenerative cues and signals.

  • New approaches to skin regeneration are likely to be underpinned by our understanding of the mechanisms responsible for wound repair.

  • Skin wounds on early mammalian embryos heal perfectly with no scars, whereas wounds to adult mammals scar.

  • The growth factor profile in a healing embryonic wound is very different from that in an adult wound.

  • TGF‐β3 has the ability to elicit a scar‐reducing effect and thus a regenerative healing response in mammalian skin.

  • Scars can have a significant psychological impact on patients, irrespective of whether or not they are hidden by clothing.

  • Scarring may no longer be an inevitable consequence of modern injury or surgery; a pharmaceutical approach to the prevention of human scarring is now possible.

Keywords: wound healing; scarring; transforming growth factor beta; epithelialisation; angiogenesis; growth factors; regeneration; skin

Figure 1.

The phases of wound healing in the skin involve a number of overlapping phases, including injury and coagulation (a), inflammation (b), proliferation and epithelialisation (c), angiogenesis and matrix deposition during the remodelling and maturation phases (d). Various growth factors and cytokines are expressed during these phases such as transforming growth factor beta (TGFβ1,‐2, ‐3), TGF alpha (TGFα), platelet‐derived growth factor (PDGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), tumour necrosis factor alpha (TNFα) and interleukin‐1 beta (il‐1β), interleukin 6, matrix metalloproteinases (MMP's), urokinase (uPA) and tissue type plasminogen activator (tPA).

Figure 2.

Scarring is conserved across species. Scarring response in mice 70 days following a 1 cm fullthickness incisional wound to the dorsum at the macroscopic (a) and microscopic (b) levels. Scarring response in rats 70 days following a 1 cm full thickness incisional wound to the dorsum at the macroscopic (c) and microscopic (d) levels. Scarring response in pigs 168 days following a 1 cm full thickness incisonal wound to the dorsum at the macroscopic (e) and microscopic (f) levels. Scarring response in humans 365 days following a 1 cm full thickness incisional wound to the inner aspect of the upper arm at the macroscopic (g) and microscopic (h) levels. Arrows on both the macroscopic and microscopic images define the scar edges.



Adzick NS and Longaker MT (1991) Animal models for the study of fetal tissue repair. Journal of Surgical Research 51(3): 216–222.

Alibardi L and Toni M (2005) Wound keratins in the regenerating epidermis of lizard suggest that the wound reaction is similar in the tail and limb. Journal of Experimental Zoology. Part A, Comparative Experimental Biology 303(10): 845–860.

Alonso L and Fuchs E (2003) Stem cells in the skin: waste not, Wnt not. Genes & Development 17: 1189–1200.

Auger FA, Lacroix D and Germain L (2009) Skin substitutes and wound healing. Skin Pharmacology and Physiology 22(2): 94–202.

Barrientos S, Stojadinovic O, Golinko MS, Brem H and Tomic‐Canic M (2008) Growth factors and cytokines in wound healing. Wound Repair and Regeneration 16(5): 585–601.

Brockes JP and Kumar A (2005) Appendage regeneration in adult vertebrates and implications for regenerative medicine. Science 310(5756): 1919–1923.

Bucala R, Spiegel LA, Chesney J, Hogan M and Cerami A (1994) Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Molecular Medicine 1(1): 71–81.

Buchanan EP, Longaker MT and Lorenz HP (2009) Fetal skin wound healing. Advances in Clinical Chemistry 48: 137–161.

Butler CE and Orgill DP (2005) Simultaneous in vivo regeneration of neodermis, epidermis, and basement membrane. Advances in Biochemical Engineering/Biotechnology 94: 23–41.

Campos I, Geiger JA, Santos AC, Carlos V and Jacinto A (2010) Genetic screen in Drosophila melanogaster uncovers a novel set of genes required for embryonic epithelial repair. Genetics 184(1): 129–140.

Caplan AI (2003) Embryonic development and the principles of tissue engineering. Novartis Foundation Symposium 249: 17–25.

Carre AL, James AW, MacLeod L et al. (2010) Interaction of wingless protein (Wnt), transforming growth factor‐beta1, and hyaluronan production in fetal and postnatal fibroblasts. Plastic and Reconstructive Surgery 125(1): 74–88.

Chettibi S and Ferguson MWJ (1999) Wound repair: an overview. In: JI Gallin and R Snyderman (eds) Inflammation: Basic Principles and Clinical Correlates, 3rd edn, pp. 864–881. Philadelphia: Lippincott Williams & Wilkins.

Colwell AS, Longaker MT and Lorenz HP (2003) Fetal wound healing. Frontiers in Bioscience 8: s1240–s1248.

Cooper L, Johnson C, Burslem F and Martin P (2005) Wound healing and inflammation genes revealed by array analysis of ‘macrophageless’ PU1 null mice. Genome Biology 6(1): R5.

Dudas M, Wysocki A, Gelpi B and Tuan TL (2008) Memory encoded throughout our bodies: molecular and cellular basis of tissue regeneration. Pediatric Research 63(5): 502–512.

Duncan JA, Bond JS, Mason T et al. (2006) Visual analogue scale scoring and ranking: a suitable and sensitive method for assessing scar quality? Plastic and Reconstructive Surgery 118(4): 909–918.

Durani P, McGrouther DA and Ferguson MW (2009) The patient scar assessment questionnaire: a reliable and valid patient‐reported outcomes measure for linear scars. Plastic and Reconstructive Surgery 123(5): 1481–1489.

Fathke C, Wilson L, Shah K et al. (2006) Wnt signaling induces epithelial differentiation during cutaneous wound healing. BMC Cell Biology 7: 4.

Fausto N (2000) Liver regeneration. Hepatology 32(suppl. 1): 19–31.

Ferguson MW, Duncan J, Bond J et al. (2009) Prophylactic administration of avotermin for improvement of skin scarring: three double‐blind, placebo‐controlled, phase I/II studies. Lancet 373(9671): 1264–1274.

Ferguson MWJ and O'Kane S (2004) Scar‐free healing: from embryonic mechanisms to adult therapeutic intervention. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 29(359(1445)): 839–850.

Ferguson MWJ, Whitby DJ, Shah M et al. (1996) Scar formation: the spectral nature of fetal and adult wound repair. Plastic and Reconstructive Surgery 97: 854–860.

Fujimori Y, Ueda K, Fumimoto H, Kubo K and Kuroyanagi Y (2006) Skin regeneration for children with burn scar contracture using autologous cultured dermal substitutes and superthin auto‐skin grafts: preliminary clinical study. Annals of Plastic Surgery 57(4): 408–414.

Garg HG and Longaker MT (2000) Scarless Wound Healing. New York: Marcel Dekker.

Godwin JW and Brockes JP (2006) Regeneration, tissue injury and the immune response. Journal of Anatomy 209(4): 423–432.

Goss RJ and Grimes LN (1975) Epidermal downgrowths in regenerating rabbit ear holes. Journal of Morphology 146: 533–542.

Han M, Yang X, Taylor G et al. (2005) Limb regeneration in higher vertebrates: developing a roadmap. Anatomical Record (Part B, New Anatomist) 287B: 14–24.

Hudon V, Berthod F, Black AF et al. (2003) A tissue engineered endothelialized dermis to study the modulation of angiogenic and angiostatic molecules on capillary‐like tube formation in vitro. British Journal of Dermatology 148(6): 1094–1104.

MacNeil S (2007) Progress and opportunities for tissue‐engineered skin. Nature 445(7130): 870–880.

Martin P, D'Souza D, Martin J et al. (2003) Wound healing in the PU.1 null mouse‐tissue repair is not dependent on inflammatory cells. Current Biology 1(13): 1122–1128.

Mast BA and Schultz GS (1996) Interactions of cytokines, growth factors and proteases in acute and chronic wounds. Wound Repair and Regeneration 20: 411–420.

McCallion RL and Ferguson MWJ (1996) Fetal wound healing and the development of antiscarring therapies for adult wound healing. In: RAF Clark (ed.) The Molecular and Cellular Biology of Wound Repair, pp. 561–600. New York: Plenum Press.

Metcalfe AD and Ferguson MW (2007) Tissue engineering of replacement skin: the crossroads of biomaterials, wound healing, embryonic development, stem cells and regeneration. Journal of the Royal Society, Interface/The Royal Society 4(14): 413–437.

Mori R, Shaw TJ and Martin P (2008) Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring. Journal of Experimental Medicine 205(1): 43–51.

O'Ceallaigh S, Herrick SE, Bluff JE, McGrouther DA and Ferguson MW (2006) Quantification of total and perfused blood vessels in murine skin autografts using a fluorescent double‐labeling technique. Plastic and Reconstructive Surgery 117(1): 140–151.

Occleston NL, Fairlamb D, Hutchison J, O'Kane S and Ferguson MW (2009) Avotermin for the improvement of scar appearance: a new pharmaceutical in a new therapeutic area. Expert Opinion on Investigational Drugs 18(8): 1231–1239.

Ono I, Akasaka Y, Kamiya T et al. (2009) De novo follicular regeneration of the skin by wingless int 3 and bone morphogenetic protein 2 genes introduced into dermal fibroblasts and fibroblast growth factor‐2 protein. Wound Repair and Regeneration 17(3): 436–446.

Pellegrini G, Bondanza S, Guerra L and De Luca M (1998) Cultivation of human keratinocyte stem cells: current and future clinical applications. Medical & Biological Engineering & Computing 36(6): 778–790.

Pellegrini G and De Luca M (2010) Human embryonic stem cell‐derived keratinocytes: how close to clinics? Cell Stem Cell 6(1): 8–9.

Pellegrini G, Ranno R, Stracuzzi G et al. (1999) The control of epidermal stem cells (holoclones) in the treatment of massive full‐thickness burns with autologous keratinocytes cultured on fibrin. Transplantation 68(6): 868–879.

Quan TE, Cowper SE and Bucala R (2006) The role of circulating fibrocytes in fibrosis. Current Rheumatology Reports 8(2): 145–150.

Redd MJ, Cooper L, Wood W, Stramer B and Martin P (2004) Wound healing and inflammation: embryos reveal the way to perfect repair. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 359(1445): 777–784.

Sato M (2006) Upregulation of the Wnt/beta‐catenin pathway induced by transforming growth factor‐beta in hypertrophic scars and keloids. Acta dermato‐venereologica 86(4): 300–307.

Schaffer CJ and Nanney LB (1996) Cell biology of wound healing. International Review of Cytology 169: 151–181.

Supp DM and Boyce ST (2005) Engineered skin substitutes: practices and potentials. Clinics in Dermatology 23: 403–412.

Sweitzer SM, Fann SA, Borg TK, Baynes JW and Yost MJ (2006) What is the future of diabetic wound care? Diabetes Educator 32(2): 197–210.

Tremblay PL, Hudon V, Berthod F, Germain L and Auger FA (2005) Inosculation of tissue engineered capillaries with the host's vasculature in a reconstructed skin transplanted on mice. American Journal of Transplantation 5(5): 1002–1010.

Werner S and Grose R (2003) Regulation of wound healing by growth factors and cytokines. Physiological Reviews 83(3): 835–870.

Whitby DJ and Ferguson MW (1991) The extracellular matrix of lip wounds in fetal, neonatal and adult mice. Development 112(2): 651–668.

Wilgus TA (2007) Regenerative healing in fetal skin: a review of the literature. Ostomy/Wound Management 53(6): 16–31.

Wilgus TA, Bergdall VK, Dipietro LA and Oberyszyn TM (2005) Hydrogen peroxide disrupts scarless fetal wound repair. Wound Repair and Regeneration 13(5): 513–519.

Yang L, Scott PG, Giuffre J et al. (2002) Peripheral blood fibrocytes from burn patients: identification and quantification of fibrocytes in adherent cells cultured from peripheral blood mononuclear cells. Laboratory Investigation; A Journal of Technical Methods and Pathology 82(9): 1183–1192.

Zheng Y, Du X, Wang W et al. (2005) Organogenesis from dissociated cells: generation of mature cycling hair follicles from skin‐derived cells. Journal of Investigative Dermatology 124(5): 867–876.

Further Reading

Fu X and Li H (2009) Mesenchymal stem cells and skin wound repair and regeneration: possibilities and questions. Cell Tissue Research 335(2): 317–321.

Gurtner GC, Werner S, Barrandon Y and Longaker MT (2008) Wound repair and regeneration. Nature 453(7193): 314–321.

Mansbridge J (2008) Skin tissue engineering. Journal of Biomaterials Science. Polymer Edition 19(8): 955–968.

Occleston NL, Laverty HG, O'Kane S and Ferguson MW (2008) Prevention and reduction of scarring in the skin by transforming growth factor beta 3 (TGFbeta3): from laboratory discovery to clinical pharmaceutical. Journal of Biomaterials Science. Polymer Edition 19(8): 1047–1063.

Occleston NL, O'Kane S, Goldspink N and Ferguson MW (2008) New therapeutics for the prevention and reduction of scarring. Drug Discovery Today 13(21–22): 973–981.

Paquet‐Fifield S, Schlüter H, Li A et al. (2009) A role for pericytes as microenvironmental regulators of human skin tissue regeneration. Journal of Clinical Investigation 119(9): 2795–2806.

Shaw TJ and Martin P (2009) Wound Repair at a glance. Journal of Cellular Science 122(Part 18): 3209–3213.

Sorrell JM and Caplan AI (2009) Fibroblasts: a diverse population at the center of it all. International Review of Cell and Molecular Biology 276: 161–214.

Stappenbeck TS and Miyoshi H (2009) The role of stromal stem cells in tissue regeneration and wound repair. Science 324(5935): 1666–1669.

Wilgus TA (2008) Immune cells in the healing skin wound: influential players at each stage of repair. Pharmacological Research 58(2): 112–116.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Metcalfe, Anthony D, and Ferguson, Mark WJ(Jan 2011) Regeneration of Mammalian Skin. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001109.pub2]