139
6
RETPAHC
Key references
be transported out again to prevent calcium overload. This is accom- ment and withdraw from the cell cycle only after birth. This is markedly
plished primarily by a sodium–calcium exchanger (NCX) in the sarco- different from skeletal muscle development, when differentiation,
lemma, and to a much lesser extent by a sarcolemmal calcium ATPase. including the activation of muscle-specific genes, coincides with with-
These act more slowly than SERCA, continuously removing calcium drawal from the cell cycle. During fetal maturation, successive changes
from the cell during the diastolic interval as calcium slowly leaks from in gene expression give rise to the characteristics of fetal, neonatal and
the sarcoplasmic reticulum. adult myocardium, and are responsible for the divergence of the proper-
The extent of the elevation of cytosolic calcium and therefore ties of atrial and ventricular muscle cells.
force generation during systole is determined by both the size of the The regulatory mechanisms underlying differentiation of cardiac
initial stimulus (amount of calcium entering through L-type channels) muscle appear to be distinct from those of skeletal muscle. It is antici-
and the amount of calcium stored within the sarcoplasmic reticulum. pated that counterparts will be found for the transcriptional factors
The greater the amount stored, the more is available for release. This Myf-5, myogenin, MyoD and Myf-6, which are responsible for inducing
provides an intrinsic mechanism for matching any increase in heart differentiation of skeletal muscle. It is known that Tbx5 and Nkx2–5
rate with a progressive increase in contractile force. At higher heart are required for formation of atrial and ventricular myocardium (see
rates, more calcium enters per unit time, but as the diastolic interval Fig. 52.13).
is reduced there is less time for calcium to be removed from the Concurrent with the development of contractile proteins, cardiac
cell by the sarcolemmal sodium–calcium exchanger. The amount of myocytes develop numerous specific intracellular vesicles containing
calcium stored in the sarcoplasmic reticulum therefore increases, so substances shown to induce natriuresis and diuresis, and a family of
more can be released during systole. Increased heart rate is therefore polypeptides generally known as atrial natriuretic peptides. These vesi-


coupled with an increase in force, a phenomenon called the staircase cles develop from the Golgi complex in both atria and ventricles during
response. fetal life but become restricted to atrial muscle in the adult. Atrial
The most potent physiological means of enhancing cardiac con- natriuretic peptide is measurable when the heart is recognizably
tractility is through the action of β-adrenergic agents, specifically the four-chambered; almost all cells within the atria are capable of its
sympathetic neurotransmitter noradrenaline (norepinephrine) and cir- synthesis.
culating adrenaline (epinephrine). Activation of β-adrenergic receptors The impulse-generating (AV node) and conducting systems of the
produces cyclic adenosine monophosphate (cAMP), which enhances heart (AV node; bundle of His, Purkinje fibres) are formed from cardiac
calcium influx via L-type calcium channels during depolarization, so myocytes that differ in their morphology from the working myocar-
stimulating greater release from the sarcoplasmic reticulum. In addi- dium of the heart chambers. Cells of the SA and AV nodes tend to be
tion, cyclic AMP enhances the activity of SERCA via promoting phos- smaller with slow cell-to-cell electrical conduction, whilst those of the
phorylation of an associated protein, phospholamban. This enables a bundle of His and Purkinje fibres are larger in diameter with very rapid
more rapid reduction of the cytosolic calcium pump and accelerated electrical conduction.
relaxation, which is important when the heart rate is increased. Phos-
phorylation of troponin-I on the thin filaments also increases the rate
of cross-bridge cycling, further accelerating relaxation. CARDIAC PLASTICITY AND REGENERATION
OF CARDIAC MUSCLE
Dysfunction of cardiac muscle: excitation–
contraction coupling in disease
The heart exhibits a significant degree of plasticity. Physiological and
pathophysiological stimuli can initiate cardiac remodelling (reviewed
In coronary heart disease the myocardium may be inadequately per- in Hill and Olson (2008)). For example, increased loads as a result of
fused (myocardial ischaemia), leading to energy deficit, loss of contrac- exercise training or pregnancy induce physiological hypertrophy of the


tility and eventually cell death. The process may culminate in heart, where the ventricular walls thicken due to an increase in the size
irretrievable myocardial damage and progress to heart failure, which is (but not number) of cardiac muscle cells. Conversely, hypertrophy
the inability to provide adequate cardiac output for the tissues. resulting from cardiac damage, high blood pressure and/or extended
activation of neurohumoral compensatory mechanisms (e.g. sympa-
thetic stimulation, production of angiotensin II and aldosterone) can
ORIGIN OF CARDIAC MUSCLE be maladaptive, increasing the risk and rate of progression of heart
failure and sudden death due to arrhythmias.
Cardiac myocytes differentiate from the splanchnopleuric coelomic In skeletal muscle, a population of precursor cells (satellite cells) is
epithelial cells of the pericardium initially subjacent to the endoderm retained in adult life, constituting a pool of myoblasts capable of divid-
(see Fig. 52.6). As the primitive heart tube is formed, the presumptive ing, fusing with existing muscle fibres and initiating regeneration after
myocardial cells start to express genes that encode characteristic myo- damage. It was thought that cardiac muscle lacked an equivalent popu-
cardial proteins, including myosin, actin, troponin and other compo- lation of cells and was therefore incapable of regeneration. There is
nents of the contractile apparatus. Myofibrils begin to appear in the some evidence that the heart does contain endogenous progenitor cells
developing myoblasts, and the first functional heart beats start soon capable of regenerating myocardial function (Oh et al 2004), although
afterwards. to a very limited extent compared to skeletal muscle and insufficient to
Committed cardiac myoblasts do not fuse to form multinucleated restore heart function after ischaemic or other injury. It has been sug-
myotubes, as occurs in skeletal muscle, but remain as single cells gested that there is a slow but continuous renewal of cardiac muscle
coupled physically and electrically through intercellular junctions. Dif- cells throughout life even in healthy individuals, with a turnover of
ferentiated cardiac myocytes continue to divide during fetal develop- between 0.4 and 1% per year (Bergmann et al 2009).
KEY REFERENCES


Berridge MJ 2008 Smooth muscle cell calcium activation mechanisms. Figueroa XF, Duling BR 2009 Gap junctions in the control of vascular func-
J Physiol 586:5047–61. tion. Antioxid Redox Signal 11:251–66.
A review of the mechanisms contributing to regulation of smooth muscle cell A review of the structure and role of smooth muscle, endothelial cell and
intracellular calcium, including sub-sarcolemmal signalling microdomains myoendothelial gap junctions in the regulation of vascular function.
and calcium oscillations.
Gunst SJ, Zhang W 2008 Actin cytoskeletal dynamics in smooth muscle: a
Bers DM 2002 Cardiac excitation–contraction coupling. Nature 415: new paradigm for the regulation of smooth muscle contraction. Am J
198–205. Physiol 295:C576–C87.
A review of the cellular mechanisms underlying cardiac muscle activation by A review of the smooth muscle cytoskeleton and its component proteins, with
an action potential and the elevation of cytosolic calcium. particular reference to its dynamic properties and role in contractile
function.
Brutsaert DL 2003 Cardiac endothelial–myocardial signaling: its role in
cardiac growth, contractile performance and rhythmicity. Physiol Rev Owens GK, Kumar MS, Wamhoff BR 2004 Molecular regulation of vascular
83:59–115. smooth muscle cell differentiation in development and disease. Physiol
A review of the important contributions that the endocardium and Rev 84:767–801.
microvascular endothelial cells make to the regulation of cardiac muscle A review of the development of vascular smooth muscle, its regulation by
function. multiple signals and how this is altered in disease.


Smooth muscle and the cardiovascular and lymphatic systems
139.e1
6
RETPAHC
The body responds to this challenge with a variety of neurohumoral This sequence of events has led to development of agents that act
mechanisms, including increased sympathetic stimulation to the heart, via increasing the binding of troponin-C to calcium, rather than by
increasing heart rate and contractility via noradrenaline (norepine- increasing calcium. However, therapy for chronic heart failure is still
phrine; see above). Treatment includes administration of positive ino- currently focused on limiting disease progression, largely by interrupt-
tropic agents (drugs that increase contractility) such as β-adrenergic ing neurohumoral compensation mechanisms. Paradoxically, this
agonists and phosphodiesterase inhibitors that prevent the breakdown includes β-adrenergic receptor antagonists, and also antagonists to
of cyclic AMP. The classical positive inotropic drug is digitalis (digoxin), angiotensin II and aldosterone (reviewed in Francis (2001)), which may
which at therapeutic doses causes partial inhibition of the sodium inhibit cardiac remodelling (see below).
pump (sodium–potassium ATPase) that maintains the ionic gradient Both increased mechanical stress and circulating or local mediators
across the sarcolemma. This leads to a reduced sodium concentration can initiate the gene transcription and protein synthesis associated with
gradient, impairing operation of the sarcolemmal sodium–calcium cardiac hypertrophy and remodelling. At least part of the response is
exchanger. Less calcium is therefore extruded from the cell, so more is mediated through calcium-dependent mechanisms involving cal-
left in the sarcoplasmic reticulum for release during systole, increasing cineurin, and isoforms of protein kinase C and calcium–calmodulin-
force. However, positive inotropes are now only used in the short term dependent kinase, but growth factors, inflammatory cytokines and
because, if used chronically, they can hasten progression of the disease. other humoral mediators also activate complex signalling cascades that
The following explains why this is the case. modify activity of transcription factors. Notably, physiological and
An energy deficit has far-reaching consequences beyond the inhibi- pathological cardiac remodelling show significant differences in gene
tion of actin and myosin interactions. ATP is vital for many cellular transcription and expression of certain proteins; pathological hypertro-


processes: in particular, the activities of the sodium pump and SERCA. phy is associated with phenotypic switching towards fetal and less
Impaired operation of the sodium pump leads to reduced extrusion of efficient isoforms of contractile proteins such as myosin heavy chain
calcium (see above). Inhibition of SERCA impairs calcium reuptake into (Hill and Olson 2008).
the sarcoplasmic reticulum and relaxation at the end of systole. The net Chronic heart failure is regarded as irreversible and progressive, and
effect is calcium overload. Mitochondria can mitigate the effects by pathological cardiac remodelling plays a major role in its progression.
taking up calcium, but eventually this causes mitochondrial damage Therapy is largely focused on agents that suppress pro-remodelling
and so worsens the energy deficit. As ATP falls further, operation of the pathways (e.g. β-blockers, angiotensin converting enzyme inhibitors,
sodium pump declines, the ionic gradient is dispersed and the cell aldosterone antagonists) and therefore slow progression (Francis 2001).
depolarizes, causing calcium entry through L-type channels, which However, recent developments have raised hope for future treatments
worsens the calcium overload and leads to cell death. Positive ino- that might reverse cardiac damage.
tropes, by increasing both cytosolic calcium and energy requirements,
will clearly worsen the situation.


SmooTH muSClE And THE CARdiovASCulAR And lymPHATiC SySTEmS
140
1
noiTCES
Pober JS, Sessa WC 2007 Evolving functions of endothelial cells in inflam- Scaal M, Christ B 2004 Formation and differentiation of the avian dermo-
mation. Nat Rev Immunol 7:803–15. myotome. Anat Embryol 208:411–24.
A review of endothelial cells as active participants in and regulators of Presentation of evidence that the epithelial plate of the somite is the
inflammatory processes and cells, and their phenotypic changes during embryological origin of endothelial and smooth muscle cells.
transition from innate to adaptive immunity.
Vestweber D 2007 Adhesion and signaling molecules controlling the trans-
Saharinen P, Tammela T, Karkkainen MJ et al 2004 Lymphatic vasculature: migration of leukocytes through endothelium. Immunol Rev 218:
development, molecular regulation and role in tumor metastasis and 178–96.
inflammation. Trends Immunol 25:387–95. A review of the range of endothelial cell surface adhesion and signalling
A comprehensive but concise review of the role, regulation and development proteins and their interaction with leukocytes.
of the lymphatic system.


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6
RETPAHC
REFERENCES
Bergmann O, Bhardwaj RD, Bernard S et al 2009 Evidence for cardiomyocyte Owens GK, Kumar MS, Wamhoff BR 2004 Molecular regulation of vascular
renewal in humans. Science 324:98–102. smooth muscle cell differentiation in development and disease. Physiol
Berridge MJ 2008 Smooth muscle cell calcium activation mechanisms. Rev 84:767–801.
J Physiol 586:5047–61. A review of the development of vascular smooth muscle, its regulation by
A review of the mechanisms contributing to regulation of smooth muscle cell multiple signals and how this is altered in disease.
intracellular calcium, including sub-sarcolemmal signalling microdomains Pan WR, Taylor GI 2009 The angiosomes of the thigh and buttock. Plast
and calcium oscillations. Reconstr Surg 123:236–49.
Bers DM 2002 Cardiac excitation–contraction coupling. Nature 415: Peter AK, Cheng H, Ross RS et al 2011 The costamere bridges sarcomeres to
198–205. the sarcolemma in striated muscle. Prog Pediatr Cardiol 31:83–8.
A review of the cellular mechanisms underlying cardiac muscle activation by Pfarr KM, Debrah AY, Specht S et al 2009 Filariasis and lymphoedema. Para-
an action potential and the elevation of cytosolic calcium. site Immunology 31:664–72.
Brutsaert DL 2003 Cardiac endothelial–myocardial signaling: its role in Pober JS, Sessa WC 2007 Evolving functions of endothelial cells in inflam-
cardiac growth, contractile performance and rhythmicity. Physiol Rev mation. Nat Rev Immunol 7:803–15.
83:59–115. A review of endothelial cells as active participants in and regulators of
A review of the important contributions that the endocardium and inflammatory processes and cells, and their phenotypic changes during
microvascular endothelial cells make to the regulation of cardiac muscle transition from innate to adaptive immunity.
function.
Sadler JE 2005 von Willebrand factor: two sides of a coin. J Thromb Haemost


Duffield JS 2012 The elusive source of myofibroblasts: problem solved? 3:1702–9.
Nature Medicine 18:1178–80. Saharinen P, Tammela T, Karkkainen MJ et al 2004 Lymphatic vasculature:
Figueroa XF, Duling BR 2009 Gap junctions in the control of vascular func- development, molecular regulation and role in tumor metastasis and
tion. Antioxid Redox Signal 11:251–66. inflammation. Trends Immunol 25:387–95.
A review of the structure and role of smooth muscle, endothelial cell and A comprehensive but concise review of the role, regulation and development
myoendothelial gap junctions in the regulation of vascular function. of the lymphatic system.
Francis GS 2001 Pathophysiology of chronic heart failure. Am J Med 110: Samarel AM 2005 Costameres, focal adhesions, and cardiomyocyte mech-
37S–46S. anotransduction. Am J Physiol Heart Circ Physiol 289:2291–301.
Fuller LC 2005 Podoconiosis: endemic nonfilarial elephantiasis. Curr Opin Scaal M, Christ B 2004 Formation and differentiation of the avian dermo-
Infectious Dis 18:119–22. myotome. Anat Embryol 208:411–24.
Gunst SJ, Zhang W 2008 Actin cytoskeletal dynamics in smooth muscle: Presentation of evidence that the epithelial plate of the somite is the
a new paradigm for the regulation of smooth muscle contraction. embryological origin of endothelial and smooth muscle cells.
Am J Physiol 295:C576–C87. Sparrow MP, Weichselbaum M, McCray PB Jr. 1999 Development of the
A review of the smooth muscle cytoskeleton and its component proteins, with innervation and airway smooth muscle in human fetal lung. Am J Respir
particular reference to its dynamic properties and role in contractile Cell Mol Biol 20:550–60.
function.
Stegemann JP 2005 Mechanical, biochemical, and extracellular matrix effects
Györke S, Terentyev D 2008 Modulation of ryanodine receptor by luminal on vascular smooth muscle cell phenotype. J Appl Physiol 98:2321–7.


calcium and accessory proteins in health and cardiac disease. Cardiovasc Stenmark KR, Fagan KA, Frid MG 2006 Hypoxia-induced pulmonary vascu-
Res 77:245–55. lar remodeling: cellular and molecular mechanisms. Circ Res 99:
Halayko AJ, Solway J 2001 Molecular mechanisms of phenotypic plasticity 675–91.
in smooth muscle cells. J App Physiol 90:358–68. Taylor GI 2003 The angiosomes of the body and their supply to perforator
Hill JA, Olson EN 2008 Cardiac plasticity. N Engl J Med 358:1370–80. flaps. Clin Plast Surg 30:331–42.
Levy SM, Taylor GI, Baudet J et al 2003 Angiosomes of the brachial plexus: Taylor GI, Palmer JH 1987 The vascular territories (angiosomes) of the body:
an anatomical study. Plast Reconstr Surg 112:1799–806. experimental studies and clinical applications. Br J Plast Surg 40:
Mahn K, Ojo OO, Chadwick G et al 2010 Ca2+ homeostasis and structural 113–41.
and functional remodelling of airway smooth muscle in asthma. Thorax Vestweber D 2007 Adhesion and signaling molecules controlling the trans-
65:547–52. migration of leukocytes through endothelium. Immunol Rev 218:
Oh H, Chi X, Bradfute SB et al 2004 Cardiac muscle plasticity in adult and 178–96.
embryo by heart-derived progenitor cells. Ann N Y Acad Sci 1015: A review of the range of endothelial cell surface adhesion and signalling
182–9. proteins and their interaction with leukocytes.


141
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CHAPTER
7
Skin and its appendages
In this chapter, the types and functions of skin in different parts of the The colour of human skin is derived from, and varies with, the
body are described first, followed by the microstructure of the epidermis amount of blood (and its degree of oxygenation) in the cutaneous
and dermis, and the appendages of skin, including the pilosebaceous circulation, the thickness of the cornified layer, and the ratio of eumela-
units and the sweat glands and nails. The development of skin, natural nin (brown/black) and pheomelanin (red/yellow). Melanin has a pro-
skin lines and age-related changes, and clinical aspects of skin, e.g. tective role against UV radiation and acts as a scavenger of harmful free
grafts, surgical skin flaps and wound healing, are also described. The radicals. Racial variations in colour are mainly due to differences in the
integumental system includes the skin and its derivatives, hairs, nails, amount, type and distribution of melanin and are genetically deter-
sweat and sebaceous glands; subcutaneous fat and deep fascia; the mined. These genetic variants may also determine the prevalence of
mucocutaneous junctions around the openings of the body orifices; and benign skin lesions such as freckles, as well as susceptibility to common
the breasts. Mucocutaneous junctions and breast tissues are covered in forms of non-melanoma skin cancers.
the appropriate regional sections. The appearance of skin is affected by many other factors, e.g. size,
shape and distribution of hairs and of skin glands (sweat, sebaceous
and apocrine), and changes associated with maturation, ageing, metab-
TYPES AND FUNCTIONS OF SKIN
olism and pregnancy. The general state of health is reflected in the
appearance and condition of the skin, and the earliest signs of many
The skin is the largest organ of the human body and constitutes approx- systemic disorders may be apparent in the skin.
imately 15% of the total body weight. In an average 70 kg person, the
skin weighs approximately 13 kg and has a surface area of about 2 m2.
CLASSIFICATION OF SKIN
It covers the entire external surface of the body, including the external


auditory meatus, the lateral aspect of the tympanic membrane and the
vestibule of the nose. It is continuous with the mucosae of the alimen- Although skin in different parts of the body is fundamentally of similar
tary, respiratory and urogenital tracts, and fuses with the conjunctiva at structure, there are many local variations in parameters such as thick-
the margins of the eyelids, and with the lining of the lacrimal canaliculi ness, mechanical strength, softness, flexibility, degree of keratinization
at the lacrimal puncta. The thickness of the skin ranges from 1.5 to (cornification), size and number of hairs, frequency and types of glands,
5.0 mm and depends mainly on its location. pigmentation, vascularity and innervation. There are two main types of
The skin forms a self-renewing interface between the body and its skin: the thick, hairless (glabrous) skin, which forms the surfaces of the
environment. It provides an effective barrier against microbial organ- palms of the hands, soles of the feet, and flexor surfaces of the digits;
isms, and protects against mechanical, chemical, osmotic, thermal and and the thinner, hairy type, which covers large areas of the body (Figs
ultraviolet radiation damage. It is an important site of immune surveil- 7.1–7.2; see Fig. 7.4).
lance against the entry of pathogens and the initiation of primary
immune responses. For instance, the skin produces various antimicro- MICROSTRUCTURE OF SKIN AND
bial peptides such as human cathelicidin LL-37, a small cationic peptide
SKIN APPENDAGES
that can prevent the immunostimulatory effects of bacterial wall mol-
ecules such as lipopolysaccharide and therefore protect against endo-
toxaemia. It can inhibit neutrophil apoptosis and stimulate angiogenesis, EPIDERMIS
tissue regeneration, and release of cytokines such as interleukin (IL)-8.
Specific innate immune defences in the skin are present throughout the The epidermis (see Fig. 7.2; Fig. 7.3) is a self-renewing stratified epithe-
epidermis, dermis, hair follicles and appendages, and in the absence of lial tissue consisting mainly of keratinocytes. Other cells within the


skin diseases or trauma, provide a resilient buffer against external epidermis include melanocytes (pigment-forming cells from the embry-
microorganisms. onic neural crest), Langerhans cells (immature antigen-presenting den-
Skin performs many biochemical synthetic processes, including the dritic cells derived from bone marrow), lymphocytes and Merkel cells.
formation of vitamin D under the influence of ultraviolet B (UVB) Merkel cells may function as sensory mechanoreceptors or possibly as
radiation and synthesis of cytokines and growth factors. Skin is the part of the dispersed neuroendocrine system and many are associated
target of a variety of hormones such as thyroxine, androgens and oes- with nerve endings. Free sensory nerve endings are sparsely present
trogens. These activities can affect the appearance and function of indi- within the epidermis. In routine histological preparations, the non-
vidual skin components, such as the sebaceous glands, the hairs and keratinocyte cells are almost indistinguishable, and appear as clear cells
the pigment-producing cells. surrounded by a space produced by shrinkage during processing. Their
Control of body temperature is an important function of skin, and cytoplasm lacks prominent filament bundles.
is effected mainly by regulation of heat loss from the cutaneous circu- The population of keratinocytes undergoes continuous renewal
lation through the rapid increase or reduction in the flow of blood to throughout life. This turnover of keratinocytes is mediated by stem cells
an extensive external surface area. This process is also assisted by that reside in the basal layer of the epidermis. These basal cells generate
sweating. In disorders such as erythroderma, in which more than 90% daughter cells, which undergo a series of biochemical and physical
of the skin is inflamed and red, insensible fluid losses can exceed changes as they migrate towards the surface of the skin to form the
several litres per days and can result in shock if treatment is not initi- various layers of the epidermis. They transform from polygonal living
ated promptly. Skin is involved in socio-sexual communication and cells to non-viable flattened squames full of intermediate filament pro-
can signal emotional states by means of muscular and vascular teins (keratins) embedded in a dense matrix of cytoplasmic proteins to
responses. It is a major sensory organ, richly supplied by nerve termi- form mature keratin. The process is known as cornification.


nals and specialized receptors for touch, temperature, pain and other The epidermis consists of several layers: the innermost layer is the
stimuli. basal layer (stratum basale) and is succeeded by the spinous or prickle
Skin has good frictional properties, assisting locomotion and manip- cell layer (stratum spinosum), granular layer (stratum granulosum),
ulation by its texture. It is elastic, and can be stretched and compressed clear layer (stratum lucidum) and cornified layer (stratum corneum),
within limits. The outer surface is covered by skin lines, some of which which is the most superficial (Fig. 7.4). The first three of these layers
are large and conspicuous while others are microscopic, or are only are metabolically active compartments through which cells pass and
revealed after manipulation or incision of the skin. change their morphology as they undergo cellular differentiation. The


Skin And iTS APPEndAgES
142
1
nOiTCES
THICK (HAIRLESS) SKIN THIN (HAIRY) SKIN
Subpapillary neural Opening (pore) Shaft of hair
plexus of sweat duct
Sweat duct
Subpapillary vascular
Dermal
plexus Friction ridge papillae
Fig. 7.1 The organization of skin, comparing the structures found in thick, hairless (plantar and palmar) skin with thin, hairy (hirsute) skin. The epidermis
has been partially peeled back to show the interdigitating dermal and epidermal papillae.
Keratinocytes
Basal layer
The basal layer or stratum basale is the innermost layer of the epidermis
and is adjacent to the dermis. It is the site of epidermal cellular prolif-
eration. This layer is in contact with a basal lamina (Fig. 7.5; see Fig.
2.8), which is a thin layer of specialized extracellular matrix, not usually
visible by light microscopy. By transmission electron microscopy, the
basal lamina consists of a clear lamina lucida (adjacent to the basal cell
plasma membrane) and a darker electron-dense lamina densa. The
basal plasma membrane of the basal keratinocytes, the extracellular
basal lamina (lamina lucida and lamina densa) and anchoring fibrils
composed of type VII collagen within the subjacent dermal matrix (the
lamina fibroreticularis), which insert into the lamina densa, collectively
form the basement membrane zone (BMZ) at the dermal–epidermal
junction. This is a highly convoluted interface, particularly in thick,
hairless skin, where dermal papillae (rete ridges) project into the epi-
dermis, interlocking with adjacent downward projections of the epider-
mis (rete pegs) (see Fig. 7.4).
The majority of basal keratinocytes (see Fig. 7.3) are columnar to
cuboidal in shape, with large (relative to their cytoplasmic volume),
mainly euchromatic nuclei and prominent nucleoli. The cytoplasm
contains variable numbers of melanosomes and keratin filament
bundles corresponding to the keratin tonofilaments of classic electron


microscopy. In the basal keratinocytes, these keratins consist mostly of
keratin 5 (K5) and keratin 14 (K14) proteins. The plasma membranes
of interconnecting cells are coupled by desmosomes while those of the
basal keratinocytes are linked to the basal lamina by hemidesmosomes
(see Figs 7.5, 1.19). Melanocytes (see Fig. 7.9), Langerhans cells (see
Figs 7.3 and 7.11) and Merkel cells (see Fig. 3.27) are interspersed
simredipE
simreD
simredopyH
Deep cutaneous Papillary layer
vascular plexus of dermis
Pacinian
corpuscle Reticular layer
of dermis
Sweat gland Sweat duct
Subcutaneous
adipose tissue
Sweat gland
Hair follicle
Arrector pili muscle Sebaceous gland
C
Fig. 7.2 The interfollicular epidermis of human thin skin. Note the thin
cornified layer (C) in comparison with the thick cornified layer in Figure
7.4 (which is at a lower magnification). (Courtesy of Mr Peter Helliwell
and the late Dr Joseph Mathew, Department of Histopathology, Royal
Cornwall Hospitals Trust, UK.)
more superficial layers of cells undergo terminal keratinization, or
cornification, which involves not only structural changes in keratino-
cytes, but also molecular and biochemical changes within the cells and
their surroundings.
The epidermal appendages (pilosebaceous units, sweat glands and
nails) are formed developmentally by the ingrowth of the epidermis.


Microstructure of skin and skin appendages
143
7
RETPAHC
Fig. 7.3 The main features of the epidermis, including its cell
layers and different cell types.
among the basal keratinocytes. Merkel cells are connected to keratino-
cytes by desmosomes, but melanocytes and Langerhans cells lack these
specialized contacts. Intraepithelial lymphocytes are present in small
numbers.
Keratinocyte stem cells are found within the basal layer of the epi-
dermis. These cells divide into progeny cells called transit (or transient)
amplifying cells, which also reside within the basal layer. Transit ampli-
fying cells undergo a few rounds of proliferation before undergoing
terminal differentiation. The activity of stem cells and transit amplifying
cells in the basal layer provides a continuous supply of differentiating
cells, which move suprabasally, eventually forming the cornified or
corneocyte layer of the epidermis. Stem cells are thought to reside
mainly in the interfollicular epidermis in the troughs of rete pegs, in
the outer root sheath bulge of the hair follicle and in sebaceous glands.
The distribution of stem cells and the size of their proliferative units
(see below) may be quite variable in human skin.
The epidermal stem cells and their differentiated progeny are organ-
ized into columns named epidermal proliferation units. Several layers
of prickle and granular cells overlie a cluster of 6–8 basal cells, forming
a columnar proliferative unit. Each group of basal cells consists of a
central stem cell with an encircling ring of transit amplifying prolifera-
tive cells and postmitotic maturing cells. From the periphery of this
unit, postmitotic cells transfer into the prickle cell layer. The normal
total epidermal turnover time is between 52 and 75 days. In some skin
disorders, the turnover rates and transit times are significantly short-
ened, e.g. in psoriasis, the total epidermal turnover time may be as
little as 8 days. The control of keratinocyte proliferation and differen-
tiation is beyond the scope of this publication but is reviewed in Fuchs
(2007).
simredipE
simreD
Detaching squame
Keratinized squame
of cornified layer
Granular layer
Langerhans cell
Prickle cell layer


Merkel cell
Basal cell layer
Basal lamina
Connective tissue
of dermis
Melanocyte Dividing Sensory nerve Basal cell
basal cell terminal in transit
Basal keratinocyte Keratins 5 and 14
CC
GG
LL
SS
BB
230-kDa bullous
PP pemphigoid antigen Plectin
Hemidesmosomal
inner plaque
Fig. 7.4 The epidermis and papillary dermis (P) of human thick skin,
showing the thick cornified layer (C, stratum corneum), the eosinophilic Hemidesmosomal
clear layer (L, stratum lucidum), the granular layer (G, stratum outer plaque
granulosum), the prickle cell layer (S, stratum spinosum) and the basal
layer (B, stratum basale). Capillary loops (arrows) are seen entering the
deep papillae (rete ridges) of the dermis, between downward-projecting
epidermal rete pegs. (Courtesy of Mr Peter Helliwell and the late Dr
Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals
Trust, UK.)
β4 integrin
Collagen XVII
CD151
Lamina lucida
α6 integrin
Lamina densa Laminin 332
Collagen VII
Dermis
Anchoring fibril
Fig. 7.5 The major features of a hemidesmosome in the basement
membrane zone (BMZ) of skin, including some of the important molecular
components. Note that laminin 332 was formerly laminin 5. (Original figure
courtesy of Masatomo Kawano.)


Skin And iTS APPEndAgES
144
1
nOiTCES
C
L
G
S
Fig. 7.6 The superficial layers of human thick skin, showing the deeply
stained keratohyalin granule-containing cells of the granular layer (G)
between the prickle cell or spinous layer (S) and the clear (or lucid, L)
and cornified (C) layers above. Note that the clear layer is only translucent
in unstained preparations and appears eosinophilic, as here, after
staining. (Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew,
Department of Histopathology, Royal Cornwall Hospitals Trust, UK.)
Prickle cell layer Fig. 7.7 A scanning electron micrograph showing the epidermal surface
The prickle cell layer, also known as the stratum spinosum (see Fig. 7.3; surrounding the aperture of a sweat duct. Note the polygonal, scale-like
Fig. 7.6), consists of several layers of closely packed keratinocytes. These keratinocytes (squames) of the superficial cornified layer.
cells are connected to each other by desmosomes, specialized cell–cell
junctions that provide tensile strength and cohesion to the layer. When
Cornified layer
skin is stained by haematoxylin and eosin and viewed by routine light
microscopy, intercellular bridges corresponding to the locations of The cornified layer (see Figs 7.3, 7.6) is the final product of epidermal
desmosomes are seen between the dehydrated keratinocytes. This differentiation. It consists of closely packed layers of flattened polyhe-
appearance gives these suprabasal keratinocytes their characteristic dral squames or corneocytes (Fig. 7.7), ranging in surface area from
spiny appearance. The cytoplasm of the keratinocytes in the prickle cell 800 to 1100 µm2. These cells overlap at their lateral margins and inter-
layer contains prominent bundles of cytokeratin filaments, mostly lock with cells of apposed layers by ridges, grooves and microvilli. In
cytokeratins 1 (K1) and 10 (K10), arranged concentrically around a thin skin, this layer may be a few cells deep, but in thick skin it may be


euchromatic nucleus and attached to the dense plaques of the desmo- more than 50 cells deep. The plasma membrane of the corneocytes
somes. The cytoplasm also contains melanosomes, either singly or appears thicker than that of other keratinocytes, partly due to the cross-
aggregated within membrane-bound organelles (compound melano- linking of a soluble precursor, involucrin, at the cytoplasmic face of the
somes). Langerhans cells (see Fig. 7.11) and occasional lymphocytes are plasma membrane, in the complex insoluble cornified envelope. The
also present in the prickle cell layer. outer surface is also covered by a monolayer of bound lipid. The inter-
cellular region contains extensive lamellar sheets of glycolipid derived
Granular layer
from the lamellar granules of the granular layer. The cells lack a nucleus
Extensive changes in keratinocyte structure occur in the 3–4 layers of and membranous organelles, and consist solely of a dense array of
flattened cells in the granular layer, also known as the stratum granu- keratin filaments embedded in a cytoplasmic matrix, which is partly
losum. The nuclei become pyknotic and begin to disintegrate. composed of filaggrin derived from keratohyalin granules.
Organelles such as ribosomes and membrane-bound mitochondria Under normal conditions, the production of epidermal keratino-
and Golgi bodies degenerate. Cytokeratin filament bundles become cytes in the basal layer is matched by the loss of corneocytes from the
more compact and associated with irregular, densely staining kerato- cornified layer. Desquamation of these cells is normally imperceptible.
hyalin granules (see Fig. 7.6). Small round granules (100 × 300 nm) When excessive, it may appear as dandruff on the scalp or the flaking
with a lamellar internal structure (lamellar granules, Odland bodies, or peeling skin that follows sunburn. In certain skin disorders such as
keratinosomes) also appear in the cytoplasm. Keratohyalin granules psoriasis, there is extensive scaling. The thickness of the cornified layer
contain a histidine-rich, sulphur-poor protein profilaggrin, which can be influenced by local environmental factors including chronic


becomes modified to filaggrin as the cell reaches the stratum corneum. scratching, which can lead to a considerable thickening of the whole
The lamellar granules release their hydrophobic glycophospholipid epidermis including the cornified layer. The soles of the feet become
contents into the intercellular space within this layer and between the much thickened if an individual habitually walks barefoot, and calluses
granular layer and the cornified layer. These glycophospholipids form develop in areas of frequent pressure, e.g. on various parts of the feet
an important component of the permeability barrier of the epidermis. from wearing tight shoes; palmar calluses in manual workers; and
Defects in the filaggrin protein, as a result of loss-of-function mutations digital calluses in guitar players.
in the filaggrin (FLG) gene, have been shown to cause ichthyosis vul-
Keratins
garis, a common dry scaly skin condition, as well as being a major risk
factor for atopic eczema. In addition, copy number variation in the FLG Epidermal keratinization has historically been the term applied to the
gene may influence the amount of filaggrin in the skin and also con- final stages of keratinocyte differentiation and maturation, during
tribute to the pathogenesis of both dry skin and eczema. The degrada- which cells are converted into tough cornified squames. However, this
tion products of filaggrin, including urocanic acid, contribute to the is now regarded as ambiguous because the term keratin is assumed to
formation of natural moisturizing factor, a key component of the epi- refer to the protein of epithelial intermediate filaments, rather than to
dermal barrier function. The functions of filaggrin are reviewed in the whole complement of proteins in the terminally differentiated cell
Brown and McLean (2012). of the stratum corneum.
Keratins are the intermediate filament proteins found in all epithe-
Clear layer
lial cells. There are two types: namely, type I (acidic) and type II (neutral/
The clear layer is only found in thick palmar or plantar skin. It repre- basic). They form heteropolymers, are co-expressed in specific pairs and


sents a poorly understood stage in keratinocyte differentiation. It stains are assembled into 10 nm intermediate filaments. Fifty-four different
more strongly than the cornified layer with acidic dyes (see Fig. 7.6). It functional keratin genes are recognized in humans. These are expressed
is more optically refractile and often contains nuclear debris. Ultrastruc- in highly specific patterns and also according to the stage of cellular
turally, the cells contain compacted keratin filaments and resemble the differentiation. Antibodies to individual keratins are useful analytical
incompletely keratinized cells that are occasionally seen in the inner- tools (Fig. 7.8). Keratins K5 and K14 are expressed by basal keratino-
most part of the cornified layer of thin skin. cytes. Keratins K1 and K10 are synthesized suprabasally. In the granular


Microstructure of skin and skin appendages
145
7
RETPAHC
E
Fig. 7.9 Melanocytes in the basal layer of thin skin, including that of the
follicular epidermis, in a biopsy of peri-auricular skin in a Caucasian male.
The pigmented melanocytes, visualized immunocytochemically using
antibody against a differentiation marker (Melan A/MART-1), extend
D
dendritic processes between keratinocytes of the basal and lower prickle
cell layers. Melanocytes are relatively inactive in this specimen; no
melanosomes are visible in the surrounding keratinocytes. (Courtesy
Fig. 7.8 Immunofluorescence microscopy of human skin showing the of Mr Peter Helliwell and the late Dr Joseph Mathew, Department of
epidermis (E), cytokeratin 14 (green staining) in the basal layer, the dermis Histopathology, Royal Cornwall Hospitals Trust, UK.)
(D) and the dermal–epidermal junction (dotted line).
layer the filaments become associated with keratohyalin granules con-
taining profilaggrin, a histidine-rich phosphorylated protein. As the
cells pass into the cornified layer, profilaggrin is cleaved by phosphatases
into filaggrin, which causes aggregation of the filaments and forms the
matrix in which they are embedded. Other types of keratin expression
occur elsewhere, particularly in hair and nails, where highly specialized
hard keratin is expressed. This becomes chemically modified and is
much tougher than in the epidermis. For a recent review of keratin
function, see Pan et al (2013).
Epidermal lipids
The epidermis serves as an important barrier to transepidermal loss of
water and other substances through the body surface (apart from in
sweating and sebaceous secretion). This is possible in part because of
the presence of an epidermal lipid layer that consists of a variety of
lipids that are synthesized in the epidermis. These include triglycerides,
fatty acids, phospholipids, cholesterol, cholesterol esters, glycosphingo-
lipids and ceramides. Furthermore, 7-dehydrocholesterol, an intermedi-


ate molecule in the cholesterol biosynthesis pathway and a precursor Fig. 7.10 An electron micrograph of a basal epidermal melanocyte,
of vitamin D, is synthesized in the skin. The content and composition showing its nucleus and cytoplasm containing melanosomes (white
of epidermal lipids change with differentiation. Phospholipids and arrows). There are no desmosomes connecting it with apposed
glycolipids first accumulate within keratinocytes above the basal layer, keratinocytes. The cytoplasm of the keratinocytes is full of dense keratin
but higher up they are broken down and are practically absent from the filaments (which are absent from the melanocyte) and transferred
cornified layer. Cholesterol and its esters, fatty acids and ceramides melanosomes. The dermo-epidermal junction is indicated (black arrows).
accumulate towards the surface and are abundant in the cornified layer. Human tissue. (Courtesy of Dr Bart Wagner, Histopathology Department,
Sheffield Teaching Hospitals, UK.)
The lamellar arrangement of the extracellular lipids is a major factor in
their barrier function. For further reading on cornified layer lipids, see
Elias et al (2014). per unit area of epidermis range from 2300 per mm2 in cheek skin to
800 per mm2 in abdominal skin. It is estimated that a single melanocyte
Melanocytes
may be in functional contact via its dendritic processes with up to 30
keratinocytes. The nucleus is large, round and euchromatic, and the
Melanocytes are melanin pigment-producing cells derived from the cytoplasm contains intermediate filaments, a prominent Golgi complex
neural crest (Figs 7.9–7.10). They are present in the epidermis and its and vesicles and associated rough endoplasmic reticulum, mitochon-
appendages, oral epithelium, some mucous membranes, uveal tract dria and coated vesicles, together with a characteristic organelle, the
(choroid coat) of the eyeball, parts of the middle and internal ear, and melanosome.
in the pial and arachnoid meninges, principally over the ventrolateral The melanosome is a membrane-bound structure that undergoes a
surfaces of the medulla oblongata. The cells of the retinal pigment sequence of developmental stages during which melanin is synthesized


epithelium, developed from the outer wall of the optic cup, also and deposited within it by a tyrosine–tyrosinase reaction. Mature
produce melanin, and neurones in different locations within the brain- melanosomes move into the dendrites along the surfaces of micro-
stem (e.g. the locus coeruleus and substantia nigra) synthesize a variety tubules and are transferred to keratinocytes through their phagocytic
of melanin called neuromelanin. In humans there are two classes, the activity (reviewed in Wu and Hammer (2014)). Each melanocyte sup-
brown–black eumelanin and the red–yellow pheomelanin, both plies melanin to approximately 35–40 neighbouring basal keratinoc-
derived from the substrate tyrosine. Most natural melanins are mixtures ytes. Keratinocytes engulf and internalize the tip of the dendrite with
of eumelanin and pheomelanin; pheomelanic pigments, trichochromes, the subsequent pinching-off of melanosomes into the keratinocyte
occur in red hair. cytoplasm. Here, they may exist as individual granules in heavily pig-
Melanocytes are dendritic cells and lack desmosomal contacts with mented skin, or be packaged within secondary lysosomes as melano-
apposed keratinocytes, though hemidesmosomal contacts with the some complexes in lightly pigmented skin. In basal keratinocytes they
basal lamina are present. In routine tissue preparations, melanocytes can be seen to accumulate in a crescent-shaped cap over the distal part
appear as clear cells in the basal layer of the epidermis. The numbers of the nucleus. As the keratinocytes progress towards the surface of the


Skin And iTS APPEndAgES
146
1
nOiTCES
epidermis, melanosomes undergo degradation, and melanin remnants squamous epithelia, including the buccal, tonsillar and oesophageal
in the cornified layer form dust-like particles. Melanosomes are degraded epithelia, as well as the cervical and vaginal mucosae, and the transi-
more rapidly in light-skinned than in dark-skinned individuals, in tional epithelium of the bladder. They are found in the conjunctiva but
whom melanosomes persist in cells of the more superficial layers. not in the cornea. In routine haematoxylin and eosin histological prep-
Melanosomes are acidic, which explains why the larger melanosomes arations, they appear as clear cells. They enter the epidermis from the
present in dark skin types are associated with a more acidic skin surface bone marrow during development to establish the postnatal popula-
(pH = 4.3), compared to lighter skin types (pH = 5.3). tion (460–1000/mm2, 2–3% of all epidermal cells, with regional vari-
Melanin protects the skin against the harmful effects of UV radiation ations), which is maintained by continual replacement from the
on DNA and is also an efficient scavenger of damaging free radicals. marrow.
However, a high concentration of melanin may adversely affect synthe- The nucleus is euchromatic and markedly indented, and the cyto-
sis of vitamin D in darker-skinned individuals living in northern lati- plasm contains a well-developed Golgi complex, lysosomes (which
tudes. Melanin pigmentation is both constitutive and facultative. often contain ingested melanosomes) and a characteristic organelle, the
Constitutive pigmentation is the intrinsic level of pigmentation and is Birbeck granule, which is the ultrastructural hallmark of the Langerhans
genetically determined, whereas facultative pigmentation represents cell. The latter are discoid or cup-shaped, or have a distended vesicle
reversible changes induced by environmental agents, e.g. UV and X- resembling the head of a tennis racket; in section they often appear as
radiation, chemicals and hormones. Racial variations in pigmentation a cross-striated rod 0.5 µm long and 30 nm wide. When stimulated by


are due to differences in melanocyte morphology and activity rather antigen, Langerhans cells migrate out of the epidermis to lymphoid
than to differences in number or distribution. In skin with naturally tissues (see Fig. 4.14). Their numbers are increased in chronic skin
heavy pigmentation, the cells tend to be larger and more dendritic, and inflammatory disorders, particularly of an immune aetiology, such as
to contain more large, late-stage melanosomes than the melanocytes of some forms of dermatitis.
paler skins. The keratinocytes in turn contain more melanosomes, indi-
vidually dispersed, whereas in light skins the majority are contained Merkel cells
within secondary lysosomes to form melanosome complexes.
The response to UV light includes immediate tanning with pigment
Merkel cells (see Commentary 1.3) are present as clear oval cells, singly
darkening and can occur within minutes as a result of photo-oxidation
or in groups, in the basal layer of the epidermis. They are also present
of pre-existing melanin. Delayed tanning occurs after about 48 hours,
in the outer root sheath of some large hair follicles. Merkel cells are
and involves stimulation of melanogenesis within the melanocytes, and
thought to derive embryologically from the epidermis, although a
transfer of additional melanosomes to keratinocytes. There may also be
neural crest origin has been considered. They can be distinguished
some increase in size of active melanocytes, and in their apparent
histologically from other clear cells (melanocytes and Langerhans cells)
numbers, mainly through activation of dormant cells. Freckles in the
only by immunohistochemical and ultrastructural criteria.
skin, particularly of red-haired individuals, are usually thought to be
The plasma membrane of a Merkel cell has short, stiff processes that
induced by UV, though they do not appear until several years after birth,
interdigitate with adjacent basal keratinocytes to which it is attached by
despite exposure. Paradoxically, melanocytes are significantly fewer in
small desmosomes. The cytoplasm contains numerous closely packed
freckles than in adjacent paler epidermis, but they are larger and more
intermediate filaments (mostly K8 and K18, and also K19 and K20)
active.
Adrenocorticotrophin (ACTH) is thought to affect melanocyte activ-


and characteristic 80–110 µm dense-core granules. The basal plasma
membrane of many Merkel cells is closely apposed to the membrane
ity, and is probably responsible for the hyperpigmentation associated
of an axonal terminal, which conveys the sensation of touch. Merkel
with pituitary and adrenal disorders. In pregnancy, higher levels of
cells are thought to function as neuroendocrine sensory receptors. They
circulating oestrogens and progesterone are responsible for the increased
are slowly adapting mechanoreceptors that respond to directional
melanization of the face, abdominal and genital skin, and the nipple
deformations of the epidermis and the direction of hair movement by
and areola, much of which may remain permanently.
releasing a transmitter from their dense-core cytoplasmic granules.
In albinism, the tyrosinase required for melanin synthesis is either
There is evidence that a subpopulation of Merkel cells lacks axonal
absent or inactive, and melanocytes, though present, are relatively qui-
contact and may serve a neuroendocrine function locally. For further
escent cells in an otherwise normal epidermis. Melanocytes decrease
reading on Merkel cells, see Lucarz and Brand (2007).
significantly in numbers in old age and are absent from grey–white hair.
Merkel cells can undergo malignant transformation (see Commen-
For further reading on melanocyte function in health and disease, see
tary 1.3), possibly triggered by the Merkel cell polyomavirus, and give
Hearing (2011).
rise to a rare and aggressive tumour called a Merkel cell carcinoma that
Langerhans cells typically presents with a painless, rapidly growing nodule on sun-
exposed sites.
Langerhans cells (Fig. 7.11) are dendritic antigen-presenting cells that
are distributed throughout the basal and prickle cell layers of the epi-
DERMIS
dermis and its appendages. They are also present in other stratified
Beneath the epidermis is the dermis (see Figs 7.1, 7.4, 7.17), which
is an irregular, moderately dense connective tissue composed of an
interwoven collagenous and elastic network in an amorphous ground
substance of glycosaminoglycans, glycoproteins and bound water. The


dermis also contains nerves, blood vessels, lymphatics and epidermal
appendages. Mechanically, the dermis provides considerable strength
to the skin by virtue of the number and arrangement of its collagen
fibres (which give it tensile strength) and its elastic fibres (which allow
it to stretch and recoil). The density of its fibre meshwork, and therefore
its physical properties, varies with different parts of the body, and with
age and gender. The dermis is vital for the survival of the epidermis,
and important morphogenetic signals are exchanged at the interface
between the two both during development and postnatally. The dermis
can be divided into two zones: a narrow, superficial papillary layer and
a deeper reticular layer. The boundary between these two zones is
indistinct.
Adult dermal collagen is mainly of types I and III, in proportions of
80–85% and 15–20% respectively. Type I collagen fibres are coarse and
found predominantly in the deeper reticular dermis, and the finer type
Fig. 7.11 Langerhans cells immunolabelled using a peroxidase method III collagen is found in the papillary dermis and around blood vessels.
for the marker protein S100, extending dendrites between keratinocytes, Type IV collagen is found in the basal lamina between epidermis and
mainly in the prickle cell layer of human thin skin. Basal layer melanocytes dermis, and around Schwann cells of peripheral nerves and endothelial
and scattered dermal cells (possibly of neural origin) are also positive for cells of vessels. Types V, VI and VII are minor collagenous components
S100. (Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, of the dermis. Elastic fibres form a fibrous network interwoven between
Department of Histopathology, Royal Cornwall Hospitals Trust, UK.) the collagen bundles throughout the dermis and are more prominent


Microstructure of skin and skin appendages
147
7
RETPAHC
in some regions, e.g. the axilla. Deficiency of type XVII collagen and layered as it passes through the inguinal regions into the thighs. It is
type VII collagen, as a result of pathogenic mutations in the COL17A1 well differentiated in the limbs and the perineum, but is thin where it
and COL7A1 genes, leads to junctional and dystrophic epidermolysis passes over the dorsal aspects of the hands and feet, the sides of the
bullosa, respectively, which manifest as trauma-induced skin fragility. neck and face, around the anus, and over the penis and scrotum. It is
Two major categories of cell are present in postnatal dermis, perma- almost absent from the external ears and atypical in the scalp and in
nent and migrant, as is typical of all general connective tissues. The the palms and soles.
permanent resident cells include cells of organized structures such as
nerves, vessels and cells of the arrector pili muscles, and the fibro blasts,
which synthesize all components of the dermal extracellular matrix. PILOSEBACEOUS UNIT
The migrant cells originate in the bone marrow (see Fig. 4.12) and
include macrophages, mast cells, eosinophils, neutrophils, T and B cells The pilosebaceous unit consists of the hair and its follicle with an
(including antibody-secreting plasma cells), and dermal interstitial den- associated arrector pili muscle, sebaceous gland and sometimes an
dritic cells, which are capable of immune surveillance and antigen apocrine gland (see Figs 7.1, 7.12). Not all elements of the unit occur
presentation. together in all body regions.
Layers of the dermis Hairs
Papillary layer Hairs are filamentous cornified structures present over almost the entire
body surface. They grow out of the skin at an angle (see Fig. 43.1), as
The papillary layer is immediately subjacent to the epidermis (see Fig.
is evident in the sloping of the hairs on the dorsum of forearm, hand
7.4). It provides mechanical anchorage, metabolic support and trophic
and fingers towards the ulnar side. Hairs are absent from several areas


maintenance to the overlying epidermis, as well as supplying sensory
of the body, including the thick skin of the palms, soles, the flexor
nerve endings and blood vessels. The cytoskeleton of the basal epider-
surfaces of the digits, the thin skin of the umbilicus, nipples, glans penis
mal keratinocytes is linked to the fibrous matrix of the papillary dermis
and clitoris, the labia minora and the inner aspects of the labia majora
through the attachment of keratin filament bundles to hemidesmo-
and prepuce. The presence, distribution and relative abundance of hair
somes, then via anchoring filaments of the basal lamina, to the anchor-
in certain regions such as the face (in males), pubis and axillae, are
ing fibrils of type VII collagen, which extend into the papillary dermis
secondary sexual characteristics that play a role in socio-sexual com-
(see Fig. 7.5). This arrangement provides a mechanically stable substra-
munication. There are individual and racial variations in density, form,
tum for the epidermis.
distribution and pigmentation. Hairs assist in thermoregulation, e.g. on
The superficial surface of the dermis is shaped into numerous papil-
the scalp they provide some protection against injury and the harmful
lae or rete ridges, which interdigitate with rete pegs in the base of the
effects of solar radiation. They also have a sensory function.
epidermis and form the dermal–epidermal junction at their interface.
Hair density varies from approximately 600 per cm2 on the face to
The papillae have round or blunt apices, which may be divided into
60 per cm2 on the rest of the body. In length, hairs range from less than
several cusps. In thin skin, especially in regions with little mechanical
a millimetre to more than a metre, and in width from 0.005 to 0.6 mm.
stress and minimal sensitivity, papillae are few and very small, while in
They can be straight, coiled, helical or wavy, and differ in colour
the thick skin of the palm and sole of the foot they are much larger,
depending on the type and degree of pigmentation. Curly hairs tend to
closely aggregated, and arranged in curved parallel lines following the


have a flattened cross-section, and are weaker than straight hairs. Over
pattern of ridges and grooves on these surfaces (see Fig. 7.1). Lying
most of the body surface, hairs are short and narrow (vellus hairs) and
under each epidermal surface ridge are two longitudinal rows of papil-
in some areas these hairs do not project beyond their follicles, e.g. in
lae, one on either side of the epidermal rete pegs, through which the
eyelid skin. In other regions they are longer, thicker and often heavily
sweat ducts pass on the way to the surface. Each papilla contains densely
pigmented (terminal hairs); these include the hairs of the scalp, the
interwoven, fine bundles of types I and III collagen fibres and some
eyelashes and eyebrows, and the postpubertal skin of the axillae and
elastic fibrils. Also present is a capillary loop (see Fig. 7.4), and in some
pubis, and the moustache, beard and chest hairs of males. The presence
sites, especially in thick hairless skin, Meissner’s corpuscle nerve
in females of coarse terminal hairs in a male-like pattern is termed
endings.
hirsutism and can be familial or a sign of an endocrine disorder involv-
Reticular layer ing excess androgen production.
The reticular layer merges with the deep aspect of the papillary layer. Hair follicle
Its bundles of collagen fibres are thicker than those in the papillary layer
The hair follicle (see Fig. 7.1; Figs 7.12–7.13A) is a downgrowth of the
and form a strong but deformable three-dimensional lattice that con-
epidermis containing a hair. It may extend deep (3 mm) into the hypo-
tains a variable number of elastic fibres. The predominant parallel
dermis, or may be superficial (1 mm) within the dermis. Typically, the
orientation of the collagen fibres may be related to the local mechanical
long axis of the follicle is oblique to the skin surface; with curly hairs
forces on the dermis and may be involved in the development of skin
it is also curved. There are cycles of hair growth and loss, during which
lines.
the follicle presents with different appearances. In the anagen phase,


the hair is actively growing and the follicle is at its maximal extent of
Hypodermis
The hypodermis (tela subcutanea; subcutaneous tissue) is a layer of Fig. 7.12 A
loose connective tissue of variable thickness that merges with the deep pilosebaceous unit in
aspect of the dermis. It is often adipose, particularly between the dermis thin, hairy skin seen at
and musculature of the body wall. It mediates the increased mobility low magnification. The
of the skin, and its adipose component contributes to thermal insula- hair follicle, hair shaft
and hair root extend
tion, acts as a shock absorber and constitutes a store of metabolic
E almost vertically
energy. Subcutaneous nerves, vessels and lymphatics travel in the hypo-
through the field, the
dermis, their main trunks lying in its deepest layer, where adipose tissue
follicle joining the
is sparse. In the head and neck, the hypodermis also contains striated
interfollicular epidermis
muscles, such as platysma, which are remnants of more extensive sheets
(E). The acini (A) of a
of skin-associated musculature found in other mammals (panniculus
sebaceous gland,
adiposus). which is also sectioned
The amount and distribution of subcutaneous fat varies according AP tangentially through its
to gender: it is generally more abundant and more widely distributed capsule (centre bottom,
in females, whereas it diminishes from the trunk to the extremities in below the portion of
males. The total amount of subcutaneous fat tends to increase in both A the hair follicle in
males and females in middle age. (At any age, the amount of adipose section), open into the
tissue reflects the quantity of lipid stored in adipocytes rather than a follicle in centre field.
change in the number of cells.) There is an association with climate Note the associated
(rather than race): superficial fat is more abundant in colder geographi- arrector pili smooth
cal regions. The hypodermis is most distinct on the lower anterior muscle (AP). Compare
abdominal wall, where it is rich in elastic tissue and appears many- with Figure 7.15.


Skin And iTS APPEndAgES
148
1
nOiTCES
A
Hair shaft
B
Inner root sheath
Outer root sheath Hair shaft
Cuticle
Cortex Hair shaft
Glassy membrane Medulla
Outer root sheath
Connective tissue
sheath Glassy membrane
Cuticle Cuticle Inner
Huxley’s layer root
H lau yexl rey’s I rn on oe tr Henle’s layer sheath
Cuticle sheath
Henle’s
Hair Cortex layer
shaft
Medulla
Connective
tissue sheath
Dermal hair Hair bulb Melanocyte
papilla
Melanocyte
Capillary loop Dermal hair
papilla
Fig. 7.13 A, The major structural features of the base of a hair follicle, showing the organization of the major layers of the hair and surrounding sheath,
arising from the hair bulb. A dermal hair papilla invaginates the bulb, and along the basal layer of the epidermis, at its interface with the dermis,
melanocytes insert their dendrites among the keratinocytes forming the hair. B, The hair bulb at the base of the human hair follicle. The dermal hair
papilla invaginates the bulb from its fibrous outer sheath, carrying a loop of capillaries. Melanocytes in the germinal matrix (equivalent to the basal layer
of interfollicular epidermis) extend dendrites into the adjacent layers of keratinocytes, to which they pass melanosomes. The layers of the hair shaft and
root sheaths are also indicated. (B, Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall
Hospitals Trust, UK.)
development. In the involuting or catagen phase, hair growth ceases of the inner root sheath. The latter are, from innermost to outer, the
and the follicle shrinks. During the resting or telogen phase, the inferior cuticle of the inner root sheath, Huxley’s layer and Henle’s layer. Henle’s
segment of the follicle is absent. This is succeeded by the next anagen layer is surrounded by the outer root sheath, which forms the cellular
phase. Further details of the hair growth cycle are given below. wall of the follicle (see Fig. 7.13). Differentiation of cells in the various


layers of the hair and its inner root sheath begins at the level of the
Anagen follicle upper bulb and is asynchronous, beginning earliest in Henle’s layer and
Huxley’s layer.
The anagen follicle has several regions. The innermost part is the infe-
rior segment, which includes the hair bulb region extending up to the
level of attachment of the arrector pili muscle at the follicular bulge. Structure of hair and its sheaths
Between this point and the site of entry of the sebaceous duct is the
A fully developed hair shaft consists of three concentric zones, which
isthmus, above which is the infundibulum, or dermal pilary canal,
are, from outermost to inner, the cuticle, cortex and medulla. Each has
which is continuous with the intraepidermal pilary canal. Below the
different types of keratin filament proteins and different patterns of
sebaceous duct, the hair shaft and follicular wall are closely connected,
cornification. In finer hairs the medulla is usually absent. The cuticle
and towards the upper end of the isthmus the hair becomes free in the
forms the hair surface and consists of several layers of overlapping
pilary canal. Below the infundibulum, the follicle is surrounded by a
cornified squames directed apically and slightly outwards (Fig. 7.14).
thick perifollicular dermal coat containing type III collagen, elastin,
Immature cuticle cells have dense amorphous granules aligned pre-
sensory nerve fibres and blood vessels, and into which the arrector pili
dominantly along the outer plasma membrane with a few filaments.
muscle fibres blend. A thick, specialized basal lamina, the glassy mem-
The cortex forms the greater part of the hair shaft and consists of numer-
brane, marks the interface between dermis and the epithelium of large
ous closely packed, elongated squames, which may contain nuclear
hair follicles.
remnants and melanosomes. Immature cortical cells contain bundles
of closely packed filaments but no dense granules, and when fully corni-
Hair bulb fied, they have a characteristic thumbprint appearance with filaments
The hair bulb forms the lowermost portion of the follicular epithelium arranged in whorls. The medulla, when present, is composed of loosely


and encloses the dermal hair papilla of connective tissue cells (Fig. aggregated and often discontinuous columns of partially disintegrated
7.13B). The dermal hair papilla is an important cluster of inductive cells containing vacuoles, scattered filaments, granular material and
mesenchymal cells, which is required for hair follicle growth in each melanosomes. Air cavities lie between the cells or even within them.
cycle throughout adult life; it is a continuation of the layer of adventi- Henle’s layer and Huxley’s layer of the inner root sheath contain
tious mesenchyme that follows the contours of the hair follicle. The irregular dense keratohyalin granules and associated filaments in the
hair bulb generates the hair and its inner root sheath. A hypothetical precornified state. At the level of the upper bulb, Henle’s layer begins
line drawn across the widest part of the hair bulb divides it into a lower to cornify, as does Huxley’s layer at the middle of the inferior follicle.
germinal matrix and an upper bulb. The germinal matrix is formed of When fully differentiated, cells of both layers have a thickened cornified
closely packed, mitotically active pluripotential keratinocytes, among envelope enclosing keratin filaments embedded in a matrix. The cells
which are interspersed melanocytes and some Langerhans cells. The of the inner root sheath cuticle undergo terminal differentiation at a
upper bulb consists of cells arising from the matrix. These migrate api- level closer to the hair bulb than that of Huxley’s layer, but lack a clear-
cally and differentiate along several lines. Those arising centrally form cut filament pattern such as is seen in the cortical cells of the hair shaft.
the hair medulla. Radially, successive concentric rings of cells give rise As they cornify, the cuticle cells of the inner root sheath and hair
to the cortex and cuticle of the hair and, outside this, to the three layers become interlocked. At about the level of entry of the sebaceous duct,


Microstructure of skin and skin appendages
149
7
RETPAHC
Fig. 7.15 A sebaceous
gland, showing a group
of secretory acini
opening into a hair
follicle (top right). The
distended sebocytes
are filled with their oily
secretion (sebum),
which is discharged
into the hair follicle by
the holocrine
disintegration of
secretory cells.
Compare with
Figure 7.12.
Fig. 7.14 A scanning electron micrograph of a scalp hair, showing details
of its surface structure. Note that the cuticular cells overlap each other;
their free ends point towards the apex of the hair. (Courtesy of Michael
Crowder MD.)
above the isthmus, the inner root sheath undergoes fragmentation, and and are shed before the growth cycle recommences. In older men,
the hair then lies free in the pilary canal. growth of hairs on the eyebrows and within the nostrils and external
The outer root sheath, beginning at the level of the upper bulb, is a ear canals increases, whereas elsewhere on the body, growth slows and
single or double layer of undifferentiated cells containing glycogen. the hairs become much finer.
Higher up the follicle it becomes multilayered. At the isthmus all Measurements of the rate of growth of individual hairs vary consid-
remaining cell layers of the follicle sheath become flattened, com- erably, probably because of the influence of the factors mentioned
pressed and attenuated. On emerging from the isthmus, the outer root above. A rate of 0.2–0.44 mm per 24 hours in males is usually given;
sheath assumes the stratified, differentiating characteristics of interfol- the higher rate occurs on the scalp. Contrary to popular myth, shaving
licular epidermis, with which it becomes continuous. At the level of does not appear to affect the growth rate and hair growth ceases after
entry of the sebaceous duct, it forms the wall of the pilary canal. death.
Hair cycle and growth of hair Sebaceous glands
Recurrent cyclic activity of hair follicles involves growth, rest, and shed-
ding of hair in phases. In humans, these occur in irregular cycles of Sebaceous glands are small saccular structures (see Figs 7.1, 7.12; Fig.


variable duration; there are regional and other variations in the length 7.15) found in the dermis. Most associate with the hair follicle and
of the individual phases. In the growing or anagen phase, follicle and arrector pili muscle to form the pilosebaceous unit. They are present
hair are as described above. Melanocytes are active only in mid-anagen, over the whole body except the thick, hairless skin of the palm, soles
and are capable of producing both pheo- and eumelanosomes, which and flexor surfaces of digits. Typically, they consist of a cluster of secre-
they pass to precortical and medullary keratinocytes. Changes in hair tory acini, which open by a short common duct into the dermal pilary
colour of an individual, usually in adolescence, are due to alterations canal of the hair follicle. They release their lipid secretory product,
in the dominant type of melanosome produced. sebum, into the canal by a holocrine mechanism. In some areas of thin
Anagen is followed by the involuting or catagen phase, during which skin that lack hair follicles, their ducts open instead directly on to the
mitotic activity of the germinal matrix ceases, the base of the hair con- skin surface, e.g. on the lips and corners of the mouth, the buccal
denses into a club that moves upwards to the level of the arrector pili mucosa, nipples (Montgomery’s glands), areolae of the female breast,
muscle, and the whole inferior segment of the follicle degenerates. The penis, inner surface of the prepuce, clitoris and labia minora. At the
dermal papilla also ascends and remains close to the base of the short- margins of the eyelids, the large, complex palpebral tarsal glands (Mei-
ened follicle and its enclosed club hair, a situation that persists during bomian glands) are of this type. They are also present in the external
the resting or telogen phase. During telogen, melanocytes become auditory meatus (ceruminous glands).
amelanotic and can be identified only ultrastructurally. At the beginning In general, the numbers of sebaceous glands in any given area reflect


of the next anagen, the epithelial cells at the base of the follicle divide the distribution of hair follicles, ranging from an average of 100/cm2
to form a secondary hair rudiment, which envelops the dermal papilla over most of the body to as many as 400–900/cm2 on the face and
to form a new hair bulb. This grows downwards, reforming the inferior scalp. They are also numerous in the midline of the back. Individual
segment of the follicle, from which a new hair grows up alongside the sebaceous glands are particularly large on the face, around the external
club hair, which is eventually shed. auditory meatus, chest and shoulders, and on the anogenital surfaces.
Postnatally, hairs exhibit regional asynchrony of cycle duration and Those on the face are often related to very small vellus hairs whose
phase leading to an irregular pattern of growth and replacement. In follicles have particularly wide apertures.
some regions, such as the scalp, the cycle is measured in years; in others, Microscopically, the glandular acini are enclosed in a basal lamina
such as general body hair, the cycle is much shorter and hairs are there- supported by a thin dermal capsule and a rich capillary network. Each
fore limited in length. At puberty, hair growth and generation of much acinus is lined by a single layer of small, flat, polygonal epithelial cells
thicker hairs occurs on the pubes and axillae in both sexes, and on the (sebocytes), which, when terminally differentiated, produce and accu-
face and trunk in males. The actions of hormones on hair growth are mulate sebum. They possess euchromatic nuclei and large nucleoli,
complex, and involve not only sex hormones, but also those of the scattered keratin filaments, free ribosomes, smooth endoplasmic reticu-
thyroid, suprarenal cortex and pituitary glands. Androgens stimulate lum and rounded mitochondria, and are attached to each other by
facial and general body hair formation. After about the first 30 years, desmosomes. Mitotically active cells give rise to progeny that move
they tend to cause the thick terminal hairs of the scalp to change to gradually towards the centre of the acinus, increasing in volume and
small vellus hairs, which produces recession from the forehead and accumulating increasingly large lipid vacuoles. The nuclei become


sometimes almost complete male pattern baldness. In females, oestro- pyknotic as the cells mature. The huge distended cells ultimately disin-
gens tend to maintain vellus hairs; postmenopausal reduction of oes- tegrate, filling the central cavity and its duct with a mass of fatty cellular
trogens may permit stronger facial and bodily hair growth. In debris (holocrine secretion; see Figs 2.6, 7.15). The process takes 2–3
mid-pregnancy, hair growth may be particularly active but later, often weeks. The secretory products pass through a wide duct lined with
post partum, an unusually large number of hairs enter the telogen phase keratinized stratified squamous epithelium into the infundibulum of


Skin And iTS APPEndAgES
150
1
nOiTCES
the hair follicle and then to the surface of the hair and the general Fig. 7.16 The coiled
epidermis. secretory portion of a
While the full range of functions in the skin remains to be clarified, sweat gland (SG) in the
sebum is a key component of the epidermal barrier, as well as having reticular dermis. The
a key role in the skin’s immune system. Sebum also contributes to a deeper-stained profiles
characteristic body odour. When first formed, sebum is a complex (above) are the origins
mixture of over 50% di- and triglycerides, with smaller proportions of of the duct. An
autonomic nerve fibre
wax esters, squalene, cholesterol esters, cholesterol and free fatty acids.
(NF) and accompanying
At birth, sebaceous glands are quite large, regressing later until stimu-
arteriole (A) and venule
lated again at puberty. At that time, sebaceous gland growth and secre-
(V) are seen below.
tory activity increase greatly in both males and females, under the
SSGG
influence of androgens (testicular and suprarenal), which act directly
on the gland. Excessive amounts of sebum may become impacted
within the duct and this, associated with hyperkeratinization, may lead
to blockage and formation of a comedone. This may become infected
and inflamed, and is the primary lesion of acne. Acne is the most
common disease caused by dysfunction of the sebocyte. Oestrogens
have an effect opposite to that of androgens, and sebum secretion is
considerably lower in women, becoming greatly decreased after the age
of 50 years. NNFF
Apocrine glands
VV
AA
Apocrine glands are particularly large glands found in the dermis or
subcutaneous fat. They are classed as a type of sweat gland. In the adult,
they are present in the axillae, perianal region, areolae, periumbilical
skin, prepuce, scrotum, mons pubis and labia minora.
An apocrine gland consists of a basal secretory coil and a straight


duct that opens into either the pilary canal above the duct of the seba- Fig. 7.17 A
ceous gland, or directly on to the skin surface if there is no associated sweat duct in a
hair. The secretory region may be as much as 2 mm wide and its coils trichrome-stained
often anastomose to form a labyrinthine network. Each coil is lined by section of thick
cuboidal secretory cells whose apical cytoplasm projects into the lumen skin. The duct
and basally is in contact with a layer of myoepithelial cells within a (SD) spirals
thick basal lamina. The secretory cells contain vacuoles, vesicles and through the
dermis and
dense granules of varying size and internal structure; the numbers and
SD epidermis, and
character vary with the cycle of synthesis and discharge. The mechanism
is visible most
of secretion is still not clear but may involve merocrine secretion of
clearly in the
granules, apocrine secretion or complete holocrine disintegration of the
cornified
cells (see Fig. 2.6).
superficial layer.
Apocrine activity is minimal before puberty, after which it is
androgen-dependent and responsive to emotional stimuli. It is control-
led by adrenergic nerves and is sensitive to adrenaline (epinephrine)
and noradrenaline (norepinephrine). The secretion is initially sterile
and odourless, but it undergoes bacterial decomposition to generate
odorous and musky compounds, including short-chain fatty acids, and
steroids such as 5α-androstenone. In many animals these are potent
pheromonal signals but their role in humans is less certain. Obstruction
of apocrine sweat ducts and associated upper hair follicles in the axillae,
breast areolae and pubic region, mainly in women, is thought to under-
lie Fox–Fordyce disease. Chronic inflammation involving the skin
bearing apocrine glands leads to a painful, occasionally debilitating
condition called hidradenitis suppurativa.
Arrector pili muscles
The arrector pili muscles are small bundles of closely packed smooth are long, unbranched, tubular structures, each with a highly coiled,


muscle cells that form oblique links between the dermal sheaths of hair secretory portion up to 0.4 mm in diameter, situated deep in the
follicles and the papillary layer of the dermis (see Figs 7.1, 7.12). They dermis or hypodermis. From there, a narrower, straight or slightly
show the typical features of smooth muscle cells and are separated by helical ductal portion emerges (see Fig. 7.1). The walls of the duct fuse
narrow spaces containing collagen fibres and unmyelinated noradren- with the base of epidermal rete pegs and the lumen passes between the
ergic sympathetic axons. keratinocytes, often in a tight spiral, particularly in thick hairless skin
The muscles are attached to the bulge region of the follicles by elastin (Fig. 7.17), and opens via a rounded aperture (pore) on to the skin
fibrils, and are directed obliquely and towards the side to which the surface (see Fig. 7.7). In thick hairless skin, sweat glands discharge
hair slopes superficially. The sebaceous gland occupies the angle along the centres of friction ridges, incidentally providing fingerprint
between the muscle and the hair follicle, and muscle contraction helps patterns for forensic analysis. Sweat glands have an important ther-
to expel the gland contents. Contraction tends to pull the hair into a moregulatory function, and their secretion enhances grip and sensitiv-
more vertical position and to elevate the epidermis surrounding it into ity of the palms and soles.
a small hillock (goose bump), dimpling the skin surface where the Eccrine sweat glands are absent from the tympanic membrane,
muscle is inserted superficially. Arrector pili muscles are absent from margins of the lips, nail bed, nipple, inner preputial surface, labia
facial, axillary and pubic hairs, eyelashes and eyebrows, and from the minora, penis and clitoris, where apocrine glands are located. They are
hairs around the nostrils and the external auditory meati. numerous elsewhere, their frequency ranging from 80 to over 600/cm2,
depending on position and genetic variation. The total number is esti-
mated to be between 1.6 and 4.5 million, and is greatest on the plantar


SWEAT GLANDS skin of the feet. There are many sweat glands on the face and flexor
aspects of the hands, and least on the surfaces of the limbs. People
The vast majority of sweat glands (Fig. 7.16) are eccrine, although their indigenous to warmer climates tend to have more sweat glands than
mode of secretion includes typical merocrine mechanisms. The glands those indigenous to cooler regions.


Microstructure of skin and skin appendages
151
7
RETPAHC
Microscopically, the secretory coil consists of a pseudostratified epi- Lateral nail fold Lunula Proximal nail fold
thelium enclosing a lumen. Three types of cell have been described:
clear cells, from which most of the secretion is derived; dark cells, which
share the same lumen; and myoepithelial cells. Clear cells are approxi-
mately pyramidal in shape, and their bases rest on the basal lamina or Distal nail Proximal
are in contact with the myoepithelial cells. Their apical plasma mem- edge nail edge
branes line lateral intercellular canaliculi, which connect with the main Eponychium
lumen. The basolateral plasma membranes are highly folded, interdigi- (cuticle)
tating with apposed clear cells, and they have the basal membrane
infoldings typical of cells involved in transcytotic fluid and ion trans- Nail plate
port from the interstitial fluid to the glandular lumen. Their cytoplasm
Proximal nail fold
contains glycogen granules, mitochondria, rough endoplasmic reticu- Distal groove
lum and a small Golgi complex, but few other organelles. The nucleus Eponychium
is round and moderately euchromatic. Dark cells are pyramidal and lie Hyponychium (cuticle)
closer to the lumen, such that their broad ends form its lining. Their
cytoplasm contains a well-developed Golgi complex, numerous vacu-
oles and vesicles, and dense glycoprotein granules, which they secrete
Distal
by a typical merocrine mechanism. Myoepithelial cells (see Figs 2.3, Eponychium (cuticle)
nail
2.4) resemble those associated with secretory acini of the salivary glands matrix Proximal nail fold
and breast, and contain abundant myofilaments. Nail bed
The intradermal sweat duct is composed of an outer basal layer and Proximal
Hyponychium
an inner layer of luminal cells connected by numerous desmosomes. nail matrix
The intraepidermal sweat duct (acrosyringium) is coiled and consists of Collagen bundle Joint


two layers of cells, which, developmentally, are different from the sur- Distal phalanx
Tendon
rounding keratinocytes and can be distinguished from them by the
presence of keratin K19. The outer cells near the surface contain kerato- Lateral nail
hyalin granules and lamellar granules, and undergo typical cornifica- groove
tion. The inner cells, from a mid-epidermal level, contain numerous
vesicles, undergo an incomplete form of cornification, and are largely Lateral nail fold Dermis
shed into the lumen at the level of the cornified epidermal layer. Distal phalanx
Sweat is a clear, odourless fluid, hypotonic to tissue fluid, and con-
Subcutaneous fat
tains mainly sodium and chloride ions, but also potassium, bicarbo-
nate, calcium, urea, lactate, amino acids, immunoglobulins and other
proteins. Excessive sweating can lead to salt depletion. Heavy metals
and various organic compounds are eliminated in sweat. When first
Proximal nail
secreted, the fluid is similar in composition to interstitial fluid. It is
matrix
modified as it passes along the duct by the action mainly of the basal
cells, which resorb sodium, chloride and some water. The hormone Dermis Distal nail matrix
aldosterone enhances this activity. The sweat glands are capable of Eponychium
Proximal nail fold
producing up to 10 litres of sweat per day, in response to thermal,
emotional and taste stimuli, mediated by unmyelinated sympathetic Collagen bundle Eponychium
cholinergic fibres. The glands also respond to adrenaline (epinephrine). (cuticle)
Thermoregulation is coordinated via a heat centre in the preoptic Lateral nail fold
region, in and near the rostral hypothalamus, which reacts to changes
in blood temperature and afferent stimuli from the skin by initiating Epidermal ridge
Glomus organ
appropriate responses such as controlling cutaneous blood supply, the
rate and volume of sweat secretion (for evaporation at the surface) and Nail bed
Nail plate
shivering.
Free edge
of the nail Hyponychium
NAIL APPARATUS Capillary
Fig. 7.18 The organization and terminology of the structures associated


Nails (Fig. 7.18) are homologous with the cornified layer of the general
with a fingernail. (With permission from Paus R, Peker S 2003 Biology of
epidermis. They consist of compacted, anucleate, keratin-filled squames hair and nails. In: Bolognia JL, Jorizzo JL, Rapini RP (eds) Dermatology.
in two or three horizontal layers. Ultrastructurally, the squames contain London: Mosby.)
closely packed filaments that lie transversely to the direction of proxi-
modistal growth, and are embedded in a dense protein matrix. Unlike
bubbles may produce white flecks. These defects move distally with the
the general epidermis, squames are not shed from the nail plate surface.
growth of the nail plate.
A variety of mineral elements including calcium are present in nail. The
The nail plate arises from compacted cornified epithelial cells derived
hardness of nail is determined by the arrangement and cohesion of the
from the dorsal, intermediate and ventral nail matrices. It is densely
layers of squames and their internal fibres, and not by the calcium
adherent to the matrices on its undersurface but becomes a free struc-
content. The water content of nail is low but nail is 10 times more
ture distal to the onychodermal band, where it separates from the nail
permeable to water than the general epidermis. The softness and elastic-
bed. The dorsal aspect of the nail plate originates from the more proxi-
ity of the nail plate are related to its degree of hydration.
mal regions of the germinal matrix, i.e. dorsal and intermediate matri-
The nail apparatus consists of the nail plate, proximal and lateral
ces, whereas the deeper, volar aspect of the plate originates from the
nail folds, nail matrix, nail bed and hyponychium.
ventral matrix.
Nail plate Nail folds
The nail plate is embedded within the proximal and lateral nail folds. The sides of the nail plate are bordered by the lateral nail folds, which
It is approximately rectangular in shape and is mostly convex in both are continuous with the proximal fold (see Fig. 7.18). They are bounded
longitudinal and transverse axes. There is considerable inter- and intra- by the attachment of the skin to the lateral aspect of the distal phalanx


individual variation (see Fig. 7.18). The thickness of the plate increases margin and the lateral nail. The proximal nail fold provides the visible
proximodistally from about 0.7 mm to 1.6 mm, although the terminal proximal border to the nail apparatus. It consists of a superficial and a
thickness varies between individuals. The surface of the nail plate may deep epidermal layer. These two layers are separated by a core of dermis.
show fine longitudinal ridges, and its undersurface is grooved by cor- The epidermis of the superficial layer lacks hair follicles and epidermal
responding ridges in the nail bed. Disturbances of growth pattern or ridges, and its cornified distal margin extends over the nail plate as the
disease may lead to transverse ridging or grooves. Minute trapped air cuticle or eponychium. The deep layer merges with the nail matrix.


Skin And iTS APPEndAgES
152
1
nOiTCES
The eponychium is bounded by the fascial attachment of the skin RSPO4 gene, which encodes R-spondin 4, have been shown to cause
to the base of the distal phalanx, distal to the insertion of the extensor recessive anonychia (absence of all fingernails and toenails). Further-
tendon, and its distal free edge. It adheres to the dorsal aspect of the more, mutations in the FZD6 gene, which encodes the Wnt receptor
nail plate and overlies the root of the nail. protein frizzled 6, have been shown to underlie the molecular basis of
autosomal recessive nail dysplasia, as well as twenty-nail dystrophy (a
Nail matrix condition that affects the nails of all the fingers and toes).
The nail matrix is the main source of the nail plate and it can be sub-
divided into three parts. Proximally, the dorsal matrix is defined as the VASCULAR SUPPLY, LYMPHATIC DRAINAGE
volar surface (undersurface) of the proximal nail fold. The intermediate AND INNERVATION
matrix (germinal matrix) starts where the dorsal matrix folds back on
itself and extends as far as the distal portion of the lunula. The ventral VASCULAR SUPPLY AND LYMPHATIC DRAINAGE
matrix (sterile matrix) is the remainder of the nail bed; it starts at the
distal border of the lunula and ends at the hyponychium.
Cutaneous blood flow amounts to approximately 5% of the cardiac
The matrix epithelium consists of typical basal and prickle layer
output. The cutaneous circulation has an important thermoregulatory
keratinocytes, among which are scattered melanocytes and Langerhans
function, and is organized so that its capacity can be rapidly increased
cells. Cornified cells of the dorsal and ventral aspects of the matrix are
or decreased by as much as 20 times, in response to a need to lose or
steadily extruded distally to form the nail plate. The proximal 50% of
conserve body heat. The ability to control skin blood flow decreases
the nail matrix contributes approximately 80% of the nail plate. This


with ageing, making older adults less able to thermoregulate adequately.
process continues into the nail bed at the distal edge of the lunula,
Lifestyle factors, such as physical activity, diet and smoking, might
which is formed where the distal portion of the ventral matrix underlies
interact with the ageing process to modulate ‘normal’ age-associated
the nail plate.
changes in the cutaneous microcirculation.
The lunula is pale, opaque and convex, and is more prominent in
The blood supply to the skin originates from three main sources: the
the thumb than the other digits. It is not known why the lunula is so
direct cutaneous, musculocutaneous and fasciocutaneous systems. The
pale compared with the more distal translucent pink nail bed. The lack
direct cutaneous system of vessels is derived from the main arterial
of colour may reflect the thickness of the epidermis in the lunula and/
trunks and accompanying veins. These vessels course in the subcutane-
or a paucity of capillaries in the dermis of the lunula.
ous fat parallel to the skin surface and are confined to certain areas of
the body, e.g. the supraorbital artery, the superficial circumflex iliac
Nail bed
artery and the dorsalis pedis artery. The musculocutaneous perforators
arise from the intramuscular vasculature, pass through the surface of
The epidermis of the nail bed extends from the distal margin of the the muscle, and pierce the deep fascia to reach the skin by spreading
lunula to the hyponychium. The distal margin of the nail bed, which out in the subcutaneous tissues. The fasciocutaneous system consists of
is the point where the nail plate becomes free of the nail bed, is called perforating branches from deeply located vessels (deep to the deep
the onychodermal band. The surface of the nail bed is ridged and fascia) that pass along intermuscular septa and then fan out at the level
grooved longitudinally, corresponding to a similar pattern on the of the deep fascia to reach the skin. Examples include the fasciocutane-
undersurface of the nail plate. This results in a tight interlocking ous perforating vessels from the radial and ulnar arteries.
between the nail plate and the underlying nail bed, protecting against The direct cutaneous vessels, musculocutaneous perforators and


microbial invasion and the collection of debris underneath the nail. fasciocutaneous perforators each contribute to six anastomosing hori-
The epidermis of the nail bed is thin and lacks a stratum granulosum. zontal reticular plexi of arterioles (Fig. 7.19), which have vascular con-
It consists of 2–3 layers of nucleated cells that lack keratohyalin gran- nections between them and which ultimately provide the blood supply
ules, and a thin cornified layer that moves distally with the growing nail to the skin. Three plexi are located in the skin itself and supply all ele-
plate. It contains an occasional sweat gland distally. ments including the sweat glands and pilosebaceous units. The subpap-
The dermis of the nail bed is anchored to the periosteum of the distal illary plexus is located at the junction of the papillary and reticular
phalanx without an underlying subcutaneous layer. It forms a tight layers of the dermis and gives off small branches that form perpendicu-
compartment, which means that infections involving the nail bed or lar capillary loops in the dermal papillae (usually one loop per papilla)
an increase in pressure, e.g. resulting from a haematoma, may cause (see Figs 7.1, 7.4; Fig. 7.20). The reticular dermal plexus is located in
severe pain, which may be relieved by the removal of part or all of the the middle portion of the dermis and is primarily venous. The deep
nail plate. The dermis of the nail bed is richly vascularized. The blood dermal plexus is located in the deepest part of the reticular dermis and
vessels are arranged longitudinally and display numerous glomus on the undersurface of the dermis. The close association between arte-
bodies, which are encapsulated arteriovenous anastomoses involved in riolar and venous plexi allows the countercurrent heat exchange between
the physiological control of peripheral blood flow in relation to tem- bloods at different temperatures.
perature. The dermis is well innervated and contains numerous sensory The remaining three plexi are the subcutaneous plexus, and two plexi


nerve endings, including Merkel endings and Meissner’s corpuscles. associated with the deep fascia. The deep fascia has a plexus on its deep
Nail bed cells differentiate towards the nail plate and contribute to its surface and a more extensive plexus superficially. This arrangement is
thickness ventrally. much more pronounced in the limbs than it is in the trunk.
The general structure and arrangement of the microvasculature is
Hyponychium described in detail in Chapter 6 and so only features particular to skin
will be considered here. In the deeper layers of the dermis, arterio-
venous anastomoses are common, particularly in the extremities
The hyponychium is the area under the free nail between the onychoder-
(hands, feet, ears, lips, nose), where vessels are surrounded by thick
mal band proximally and the distal groove. It is an epidermal ridge that
muscular coats. Under autonomic vasomotor control, these vascular
demarcates the junction between the finger pulp and the subungual
shunts, when relaxed, divert blood away from the superficial plexus and
structures.
so reduce heat loss, while at the same time ensuring maintenance of
some deep cutaneous circulation and preventing anoxia of structures
Nail growth
such as nerves. Extensive capillary anastomoses are present. Generally,
cutaneous blood flow is regulated according to thermoregulatory need
Nail growth is determined by the turnover rate of the matrix cells, which and also, in some areas of the body, according to emotional state. In
varies with digit, age, environmental temperature and season, time of very cold conditions, the peripheral circulation is greatly reduced by
day, nutritional status, trauma and various diseases. Generally, the rate vasoconstriction, but intermittent spontaneous vasodilation results in
of growth is related to the length of the digit, being fastest (approxi- periodic increases in temperature that prevent cooling to the level at
mately 0.1 mm per day) in the middle finger of the hand and slowest which frostbite might occur. This is thought to be due to a direct effect
in the little finger. Fingernails grow 3–4 times faster than toenails, more of oxygen lack on the arteriolar constrictor muscle, rather than to a
quickly in summer than in winter, and faster in the young than in the neural influence.


old. A fingernail grows out in about 6 months, whereas a toenail is The lymphatics of the skin, as elsewhere, are small terminal vessels
replaced, on average, in 18 months. that collect interstitial fluid and macromolecules for return to the cir-
Genetic keratin disorders (see Haines and Lane (2012)) may lead to culation via larger vessels. They also convey lymphocytes, Langerhans
nail dystrophies such as pachyonychia congenita, where the nails cells and macrophages to regional lymph nodes. They begin as blind-
become grossly thickened. In addition, germline mutations in the ended, endothelial-lined tubes or loops just below the papillary dermis.