Human Skin: Composition, Structure and Visualisation Methods

  • Helen K. Graham
  • Alexander Eckersley
  • Matiss Ozols
  • Kieran T. Mellody
  • Michael J. SherrattEmail author
Part of the Studies in Mechanobiology, Tissue Engineering and Biomaterials book series (SMTEB, volume 22)


In this chapter we discuss the molecular composition and structure of the epidermis, dermal-epidermal junction, dermis and hypodermis. We highlight the contribution of long-lived dermal collagens, elastic fibres, proteoglycans and hyaluronic acid to skin function and also consider the role of apparently “minor” skin components. In order to characterise both healthy skin, and the progression of disease and ageing, it is necessary to use microscopical approaches but in addition to conventional ex vivo techniques, which image in two dimensions, valuable information can be gained by complimentary non-invasive and 3D imaging technologies.


Skin structure Skin composition Epidermis Dermis Microscopy Non-invasive imaging Micro-computed X-ray tomography (microCT) 



The authors would like to acknowledge the generous financial support of Walgreens Boots Alliance.


  1. 1.
    Al-Nuaiami Y, Sherratt MJ, Griffiths CEM (2014) Skin health in older age. Maturitas 7:256–264Google Scholar
  2. 2.
    Bulterijs S, Hull R, Bjork VE, Roy AG (2015) It is time to classify biological aging as a disease. Front Genet 6:205Google Scholar
  3. 3.
    D'Errico M, Lemma T, Calcagnile A, Proietti De Santis L, Dogliotti E (2007) Cell type and DNA damage specific response of human skin cells to environmental agents. Mutat Res 614:37–47Google Scholar
  4. 4.
    Fluhr JW, Feingold KR, Elias PM (2006) Transepidermal water loss reflects permeability barrier status: validation in human and rodent in vivo and ex vivo models. Exp Dermatol 15:483–492Google Scholar
  5. 5.
    Nelson WG, Sun TT (1983) The 50- and 58-kdalton keratin classes as molecular markers for stratified squamous epithelia: cell culture studies. J Cell Biol 97:244–251Google Scholar
  6. 6.
    Proksch E, Brandner JM, Jensen JM (2008) The skin: an indispensable barrier. Exp Dermatol 17:1063–1072Google Scholar
  7. 7.
    Madison KC (2003) Barrier function of the skin: “la raison d’etre” of the epidermis. J Invest Dermatol 121:231–241Google Scholar
  8. 8.
    Elias PM (1983) Epidermal lipids, barrier function, and desquamation. J Invest Dermatol 80:44s–49sGoogle Scholar
  9. 9.
    Harding CR (2004) The stratum corneum: structure and function in health and disease. Dermatol Ther 17:6–15Google Scholar
  10. 10.
    Bollag WB, Dodd ME, Shapiro BA (2004) Protein kinase D and keratinocyte proliferation. Drug News Perspect 17:117–126Google Scholar
  11. 11.
    Cichorek M, Wachulska M, Stasiewicz A, Tymińska A (2013) Skin melanocytes: biology and development. Adv Dermatol Allergol 30:30–41Google Scholar
  12. 12.
    Collin M, Milne P (2016) Langerhans cell origin and regulation. Curr Opin Hematol 23:28–35Google Scholar
  13. 13.
    Mainiero F, Pepe A, Yeon M, Ren Y, Giancotti FG (1996) The intracellular functions of alpha6beta4 integrin are regulated by EGF. J Cell Biol 134:241–253Google Scholar
  14. 14.
    Keene DR, Sakai LY, Lunstrum GP, Morris NP, Burgeson RE (1987) Type-VII collagen forms an extended network of anchoring fibrils. J Cell Biol 104(3):611–621. CrossRefGoogle Scholar
  15. 15.
    Watson RE, Griffiths CE, Craven NM, Shuttleworth CA, Kielty CM (1999) Fibrillin-rich microfibrils are reduced in photoaged skin. Distribution at the dermal-epidermal junction. J Invest Dermatol 112:782–787Google Scholar
  16. 16.
    Briggaman RA, Wheeler CEJR (1975) The epidermal-dermal junction. J Invest Dermatol 65:71–84Google Scholar
  17. 17.
    Burgeson RE, Christiano AM (1997) The dermal-epidermal junction. Curr Opin Cell Biol 9:651–658Google Scholar
  18. 18.
    Hashmi S, Marinkovich MP (2011) Molecular organization of the basement membrane zone. Clin Dermatol 29:398–341Google Scholar
  19. 19.
    Xiong X, Wu T, He S (2013) Physical forces make rete ridges in oral mucosa. Med Hypotheses 81:883–886Google Scholar
  20. 20.
    Naylor EC, Watson RE, Sherratt MJ (2011) Molecular aspects of skin ageing. Maturitas 69:249–256Google Scholar
  21. 21.
    Mienaltowski MJ, Birk DE (2014) Structure, physiology, and biochemistry of collagens. Adv Exp Med Biol 802:5–29Google Scholar
  22. 22.
    Ramshaw JA, Shah NK, Brodsky B (1998) Gly-X-Y tripeptide frequencies in collagen: a context for host-guest triple-helical peptides. J Struct Biol 122:86–91Google Scholar
  23. 23.
    Brodsky B, Ramshaw JA (1997) The collagen triple-helix structure. Matrix Biol 15:545–554Google Scholar
  24. 24.
    Dolz R, Engel J, Kuhn K (1988) Folding of collagen IV. Eur J Biochem 178:357–366Google Scholar
  25. 25.
    Bonadio J et al (1990) Transgenic mouse model of the mild dominant form of osteogenesis imperfecta. Proc Natl Acad Sci USA 87:7145–7149Google Scholar
  26. 26.
    Bruckner-Tudeman L, Has C (2014) Disorders of the cutaneous basement membrane zone—the paradigm of epidermolysis bullosa. Matrix Biol 33:29–34Google Scholar
  27. 27.
    Kivirikko KI (1993) Collagens and their abnormalities in a wide spectrum of diseases. Ann Med 25:113–126Google Scholar
  28. 28.
    Metsaranta M, Garofalo S, Decker G, Rintala M, De Crombrugghe B, Vuorio E (1992) Chondrodysplasia in transgenic mice harboring a 15-amino acid deletion in the triple helical domain of pro alpha 1(II) collagen chain. J Cell Biol 118:203–212Google Scholar
  29. 29.
    Danielson KG, Baribault H, Holmes DF, Graham H, Kadler KE, Iozzo RV (1997) Targetted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility. J Cell Biol 136:729–743Google Scholar
  30. 30.
    Chanut-Delalande H, Bonod-Bidaud C, Cogne S, Malbouyres M, Ramirez F, Fichard A, Ruggiero F (2004) Development of a functional skin matrix requires deposition of collagen V heterotrimers. Mol Cell Biol 24:6049–6057Google Scholar
  31. 31.
    Fleischmajer R, Macdonald ED, Perlish JS, Burgeson RE, Fisher LW (1990) Dermal collagen fibrils are hybrids of type I and type III collagen molecules. J Struct Biol 105:162–169Google Scholar
  32. 32.
    Lucero HA, Kagan HM (2006) Lysyl oxidase: an oxidative enzyme and effector of cell function. Cell Mol Life Sci 63:2304–2316Google Scholar
  33. 33.
    Pinnell SR, Martin GR (1968) The cross-linking of collagen and elastin: enzymatic conversion of lysine in peptide linkage to alpha-aminoadipic-delta-semialdehyde (allysine) by an extract from bone. Proc Natl Acad Sci USA 61:708–716Google Scholar
  34. 34.
    Smith-Mungo LI, Kagan HM (1998) Lysyl oxidase: properties, regulation and multiple functions in biology. Matrix Biol 16:387–398Google Scholar
  35. 35.
    Vogel HG (1974) Correlation between tensile strength and collagen content in rat skin. Effect of age and cortisol treatment. Connect Tissue Res 2:177–182Google Scholar
  36. 36.
    Weber L, Kirsch E, Muller P, Krieg T (1984) Collagen type distribution and macromolecular organization of connective tissue in different layers of human skin. J Invest Dermatol 82:156–160Google Scholar
  37. 37.
    Gelse K, Poschl E, Aigner T (2003) Collagens—structure, function, and biosynthesis. Adv Drug Deliv Rev 55:1531–1546Google Scholar
  38. 38.
    Graham HK, Hodson NW, Hoyland JA, Millward-Sadler SJ, Garrod D, Scothern A, Griffiths CE, Watson RE, Cox TR, Erler JT, Trafford AW, Sherratt MJ (2010) Tissue section AFM: in situ ultrastructural imaging of native biomolecules. Matrix Biol 29:254–260Google Scholar
  39. 39.
    Abreeu-Velez AM, Howard MS (2012) Collagen IV in normal skin and in pathological processes. N Am J Med Sci 4:1–8Google Scholar
  40. 40.
    Loffek S, Hurskainen T, Jackow J, Sigloch FC, Schilling O, Tasanen K, Bruckner-Tuderman L, Franzke CW (2014) Transmembrane collagen XVII modulates integrin dependent keratinocyte migration via PI3K/Rac1 signaling. PLoS One 9:e87263Google Scholar
  41. 41.
    Godwin AR, Starborg T, Sherratt MJ, Roseman AM, Baldock C (2017) Defining the hierarchical organisation of collagen VI microfibrils at nanometre to micrometre length scales. Acta Biomater 52:21–32Google Scholar
  42. 42.
    Sabatelli P, Gara SK, Grumati P, Urciuolo A, Gualandi F, Curci R, Squarzoni S, Zamparelli A, Martoni E, Merlini L, Paulsson M, Bonaldo P, Wagener R (2011) Expression of the collagen VI alpha 5 and alpha 6 chains in normal human skin and in skin of patients with collagen VI-related myopathies. J Invest Dermatol 131:99–107Google Scholar
  43. 43.
    Theocharidis G, Drymoussi Z, Kao AP, Barber AH, Lee DA, Braun KM, Connelly JT (2016) Type VI collagen regulates dermal matrix assembly and fibroblast motility. J Invest Dermatol 136:74–83Google Scholar
  44. 44.
    Baldwin AK, Cain SA, Lennon R, Godwin A, Merry CL, Kielty CM (2014) Epithelial-mesenchymal status influences how cells deposit fibrillin microfibrils. J Cell Sci 127(Pt 1):158–171. CrossRefGoogle Scholar
  45. 45.
    Kielty CM, Sherratt MJ, Shuttleworth CA (2002) Elastic fibres. J Cell Sci 115:2817–2828Google Scholar
  46. 46.
    Sherratt MJ, Baldock C, Haston JL, Holmes DF, Jones CJP, Shuttleworth CA, Wess TJ, Kielty CM (2003) Fibrillin microfibrils are stiff reinforcing fibres in compliant tissues. J Mol Biol 332(1):183–193. CrossRefGoogle Scholar
  47. 47.
    Bax DV, Mahalingam Y, Cain S, Mellody K, Freeman L, Younger K, Shuttleworth CA, Humphries MJ, Couchman JR, Kielty CM (2007) Cell adhesion to fibrillin-1: identification of an Arg-Gly-Asp-dependent synergy region and a heparin-binding site that regulates focal adhesion formation. J Cell Sci 120:1383–1392Google Scholar
  48. 48.
    Lee P, Bax DV, Bilek MM, Weiss AS (2014) A novel cell adhesion region in tropoelastin mediates attachment to integrin alphaVbeta5. J Biol Chem 289:1467–1477Google Scholar
  49. 49.
    Bax DV, Bernard SE, Lomas A, Morgan A, Humphries J, Shuttleworth CA, Humphries MJ, Kielty CM (2003) Cell adhesion to fibrillin-1 molecules and microfibrils is mediated by alpha 5 beta 1 and alpha v beta 3 integrins. J Biol Chem 278:34605–34616Google Scholar
  50. 50.
    Sakamoto H, Broekelmann T, Cheresh DA, Ramirez F, Rosenbloom J, Mecham RP (1996) Cell-type specific recognition of RGD- and non-RGD-containing cell binding domains in fibrillin-1. J Biol Chem 271:4916–4922Google Scholar
  51. 51.
    Chaudhry SS, Cain SA, Morgan A, Dallas SL, Shuttleworth CA, Kielty CM (2007) Fibrillin-1 regulates the bioavailability of TGFbeta1. J Cell Biol 176:355–367Google Scholar
  52. 52.
    Massam-Wu T, Chiu M, Choudhury R, Chaudhry SS, Baldwin AK, Mcgovern A, Baldock C, Shuttleworth CA, Kielty CM (2010) Assembly of fibrillin microfibrils governs extracellular deposition of latent TGF beta. J Cell Sci 123:3006–3018Google Scholar
  53. 53.
    Cotta-Pereira G, Rodrigo G, Bittencourt-Sampaio S (1976) Oxytalan, elaunin and elastic fibers in the human skin. J Investig Dermatol 66:143–148Google Scholar
  54. 54.
    Tiedemann K, Sasaki T, Gustafsson E, Göhring W, Bätge B, Notbohm H, Timpl R, Wedel T, Schlötzer-Schrehardt U, Reinhardt DP (2005) Microfibrils at basement membrane zones interact with perlecan via fibrillin-1. J Biol Chem 280:11404–11412Google Scholar
  55. 55.
    Schaefer L, Schaefer RM (2010) Proteoglycans: from structural compounds to signaling molecules. Cell Tissue Res 339:237–246Google Scholar
  56. 56.
    Hascall VC, Majors AK, De La Motte CA, Evanko SP, Wang A, Drazba JA, Strong SA, Wight TN (2004) Intracellular hyaluronan: a new frontier for inflammation? Biochim Biophys Acta 1673:3–12Google Scholar
  57. 57.
    Oh JH, Kim YK, Jung JY, Shin JE, Kim KH, Cho KH, Eun HC, Chung JH (2011) Intrinsic aging- and photoaging-dependent level changes of glycosaminoglycans and their correlation with water content in human skin. J Dermatol Sci 62:192–201Google Scholar
  58. 58.
    Evanko SP, Tammi M, Tammi RH, Wight TN (2007) Hyaluronan-dependent pericellular matrix. Adv Drug Deliv Rev 59:1351–1365Google Scholar
  59. 59.
    Maquart FX, Monboisse JC (2014) Extracellular matrix and wound healing. Pathol Biol (Paris) 62:91–95Google Scholar
  60. 60.
    Lyon M, Rushton G, Gallagher JT (1997) The interaction of the transforming growth factor-βs with heparin/heparan sulfate is isoform-specific. J Biol Chem 272:18000–18006Google Scholar
  61. 61.
    Hynes RO, Naba A (2012) Overview of the matrisome—an inventory of extracellular matrix constituents and functions. Cold Spring Harb Perspect Biol 4:a004903Google Scholar
  62. 62.
    Rucker RB, Kosonen T, Clegg MS, Mitchell AE, Rucker BR, Uriu-Hare JY, Keen CL (1998) Copper, lysyl oxidase, and extracellular matrix protein cross-linking. Am J Clin Nutr 67:996S–1002SGoogle Scholar
  63. 63.
    Yurchenco PD (2011) Basement membranes: cell scaffoldings and signaling platforms. Cold Spring Harb Perspect Biol 3Google Scholar
  64. 64.
    Lorand L, Graham RM (2003) Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol 4:140–156Google Scholar
  65. 65.
    Doring G (1994) The role of neutrophil elastase in chronic inflammation. Am J Respir Crit Care Med 150:S114–S117Google Scholar
  66. 66.
    Kahari VM, Saarialho-Kere U (1997) Matrix metalloproteinases in skin. Exp Dermatol 6:199–213Google Scholar
  67. 67.
    Mccarty SM, Percival SL (2013) Proteases and delayed wound healing. Adv Wound Care (New Rochelle) 2:438–447Google Scholar
  68. 68.
    Mezentsev A, Nikolaev A, Bruskin S (2014) Matrix metalloproteinases and their role in psoriasis. Gene 540:1–10Google Scholar
  69. 69.
    Singh D, Srivastava SK, Chaudhuri TK, Upadhyay G (2015) Multifaceted role of matrix metalloproteinases (MMPs). Front Mol Biosci 2:19Google Scholar
  70. 70.
    Zeeuwen PLJM (2004) Epidermal differentiation: the role of proteases and their inhibitors. Eur J Cell Biol 83:761–773Google Scholar
  71. 71.
    Duca L, Floquet N, Alix AJ, Haye B, Debelle L (2004) Elastin as a matrikine. Crit Rev Oncol Hematol 49:235–244Google Scholar
  72. 72.
    Maquart FX, Simeon A, Pasco S, Monboisse JC (1999) Regulation of cell activity by the extracellular matrix: the concept of matrikines. J Soc Biol 193:423–428Google Scholar
  73. 73.
    Wells JM, Gaggar A, Blalock JE (2015) MMP generated Matrikines. Matrix Biol 44–46:122–129Google Scholar
  74. 74.
    Bonnans C, Chou J, Werb Z (2014) Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 15:786–801Google Scholar
  75. 75.
    Murphy G (2011) Tissue inhibitors of metalloproteinases. Genome Biol 12:233Google Scholar
  76. 76.
    Hubmacher D, Apte SS (2015) ADAMTS proteins as modulators of microfibril formation and function. Matrix Biol 47:34–43Google Scholar
  77. 77.
    Rijken F, Bruijnzeel PL (2009) The pathogenesis of photoaging: the role of neutrophils and neutrophil-derived enzymes. J Investig Dermatol Symp Proc 14:67–72Google Scholar
  78. 78.
    Starcher B, Conrad M (1995) A role for neutrophil elastase in solar elastosis. Ciba Found Symp 192:338–346Google Scholar
  79. 79.
    Godeau G, Hornebeck W (1988) Morphometric analysis of the degradation of human skin elastic fibres by human leukocyte elastase (EC 3-4-21-37) and human skin fibroblast elastase (EC 3-4-24). Pathol Biol (Paris) 36:1133–1138Google Scholar
  80. 80.
    Sengle G, Charbonneau NL, Ono RN, Sasaki T, Alvarez J, Keene DR, Bächinger HP, Sakai LY (2008) Targeting of bone morphogenetic protein growth factor complexes to fibrillin. J Biol Chem 283:13874–13888Google Scholar
  81. 81.
    Jensen SA, Robertson IB, Handford PA (2012) Dissecting the fibrillin microfibril: structural insights into organization and function. Structure 20(2):215–225Google Scholar
  82. 82.
    Kaartinen V, Warburton D (2003) Fibrillin controls TGF-β activation. Nat Genet 33:331–332Google Scholar
  83. 83.
    Massagué J (1998) TGF-β signal transduction. Annu Rev Biochem 67:753–791Google Scholar
  84. 84.
    Lemaire R, Bayle J, Lafyatis R (2006) Fibrillin in Marfan syndrome and tight skin mice provides new insights into transforming growth factor-beta regulation and systemic sclerosis. Curr Opin Rheumatol 18:582–587Google Scholar
  85. 85.
    Bliss E, Heywood WE, Benatti M, Sebire NJ, Mills K (2016) An optimised method for the proteomic profiling of full thickness human skin. Biol Procedures Online 18:15Google Scholar
  86. 86.
    Mikesh LM, Aramadhaka LR, Moskaluk C, Zigrino P, Mauch C, Fox JW (2013) Proteomic anatomy of human skin. J Proteomics 84:90–200Google Scholar
  87. 87.
    Aziz N, Detels R, Quint JJ, Li Q, Gietson D, Butch AW (2016) Stability of cytokines, chemokines and soluble activation markers in unprocessed blood stored under different conditions. Cytokine 84:17–24Google Scholar
  88. 88.
    Brinster RL, Brunner S, Joseph X, Levey IL (1979) Protein degradation in the mouse blastocyst. J Biol Chem 254:1927–1931Google Scholar
  89. 89.
    Kuehl L, Sumsion EN (1970) Turnover of several glycolytic enzymes in rat liver. J Biol Chem 245:6616–6623Google Scholar
  90. 90.
    Price JC, Guan S, Burlingame A, Prusiner SB, Ghaemmaghami S (2010) Analysis of proteome dynamics in the mouse brain. Proc Natl Acad Sci 107:14508–14513Google Scholar
  91. 91.
    Verzijl N, DeGroot J, Ben ZC, Brau-Benjamin O, Maroudas A, Bank RA, Mizrahi J, Schalkwijk CG, Thorpe SR, Baynes JW, Bijlsma JW, Lafeber FP, TeKoppele JM (2000) Age-related accumulation of Maillard reaction products in human articular cartilage collagen. Biochem J 350:381–387Google Scholar
  92. 92.
    Stenhouse MJ, Baxter MS (1977) Bomb 14C as a biological tracer. Nature 267:828Google Scholar
  93. 93.
    Shapiro SD, Endicott SK, Province MA, Pierce JA, Campbell EJ (1991) Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon. J Clin Investig 87:1828–1834Google Scholar
  94. 94.
    Kanitakis J (2009) Anatomy histology and immunohistochemistry of normal human skin: the epidermis. Eur J Dermatol 12(4):1–13Google Scholar
  95. 95.
    Fenske NA, Lober CW (1986) Structural and functional changes of normal aging skin. J Am Acad Dermatol 15:571–585Google Scholar
  96. 96.
    Ezure T, Amano S (2015) Increment of subcutaneous adipose tissue is associated with decrease of elastic fibres in the dermal layer. Exp Dermatol 24:924–929Google Scholar
  97. 97.
    Sherratt MJ (2015) Body mass index and elastic fibre remodelling. Exp Dermatol 24:922–923Google Scholar
  98. 98.
    Coons AH, Creech HJ, Jones RN (1941) Immunological properties of an antibody containing a fluorescent group. Proc Soc Exp Biol 47:200–202Google Scholar
  99. 99.
    Walton LA, Bradley RS, Withers PJ, Newton VL, Watson REB, Austin C, Sherratt MJ (2015) Morphological characterisation of unstained and intact tissue micro-architecture by X-ray computed micro- and nano-tomography. Sci Rep 5:10074Google Scholar
  100. 100.
    Newton VL, Bradley RS, Seroul P, Cherel M, Griffiths CE, Rawlings AV, Voegeli R, Watson RE, Sherratt MJ (2017) Novel approaches to characterize age-related remodelling of the dermal-epidermal junction in 2D, 3D and in vivo. Skin Res Technol 23:131–148Google Scholar
  101. 101.
    Disney CM, Lee PD, Hoyland JA, Sherratt MJ, Bay BK (2018) A review of techniques for visualising soft tissue microstructure deformation and quantifying strain Ex Vivo. J Microsc 272(3):165–179. doi:
  102. 102.
    Disney CM, Madi K, Bodey AJ, Lee PD, Hoyland JA, Sherratt MJ (2017) Visualising the 3D microstructure of stained and native intervertebral discs using X-ray microtomography. Sci Rep 7:16279Google Scholar
  103. 103.
    Shearer T, Bradley RS, Hidalgo-Bastida A, Sherratt MJ, Cartmell SH (2016) Commentary: 3D visualisation of soft biological structures by microCT. J Cell Sci 129:13Google Scholar
  104. 104.
    Newton VL, Mcconnell JC, Hibbert SA, Graham HK, Watson RE (2015) Skin aging: molecular pathology, dermal remodelling and the imaging revolution. G Ital Dermatol Venereol 150:665–674Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Helen K. Graham
    • 1
  • Alexander Eckersley
    • 2
  • Matiss Ozols
    • 2
  • Kieran T. Mellody
    • 1
  • Michael J. Sherratt
    • 2
    Email author
  1. 1.Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and HealthThe University of ManchesterManchesterUK
  2. 2.Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and HealthThe University of ManchesterManchesterUK

Personalised recommendations