Components of normal
human skin
Skin is the largest organ in the body. In a 70 kg
individual, the skin weighs over 5 kg and covers a surface area
approaching 2 m2. Human skin consists of a stratified, cellular
epidermis and an underlying dermis of connective tissue, separated by a dermal–
epidermal basement membrane. Beneath the dermis is a layer of subcutaneous fat,
which is separated from the rest of the body by a vestigial layer of striated
muscle.
Epidermis
The human epidermis averages 50 microns in
thickness, with a surface density of approximately 50 000 nucleated cells/mm2. The epidermis contains four major resident
populations: keratinocytes, melanocytes, Langerhans cells, and Merkel
cells. Keratinocytes, the major population, originate in a
stem-cell pool situated in the basal layer; cells that leave this pool then
undergo maturation as they migrate upward, ultimately forming the laminated
stratum corneum. Under basal conditions, differentiated keratinocytes require
about two weeks to exit the nucleated compartment and an additional two weeks
to move through the stratum corneum. It should be noted that keratinocytes have
the capacity to increase rates of proliferation and maturation to levels far
greater than this, when stimulated to do so by injury, inflammation or disease.
The skin is divided into 3 major layers: (1)
the epidermis, which serves as a barrier to prevent loss of fluid and
electrolytes and to protect against external insults such as chemicals and
microbes; (2) the dermis, which provides structural and nutritional support;
and (3) the subcutaneous fat. Adnexal structures, including hair follicles,
sebaceous glands, eccrine glands and apocrine glands, are found within the
dermis.
Histopathologic features of normal skin from three different anatomic
sites.
A comparison of
biopsy specimens from the arm (A), flank (B), and back (C) demonstrates the
increasing thickness of the dermis. However, there is a similarity with regard
to the presence of blood vessels and adnexal structures including eccrine
glands.
The epidermal layers from the surface are: (1) the stratum
corneum; (2) the granular layer (stratum granulosum); (3) the stratum spinosum;
and (4) the basal layer (stratum basale). Under basal conditions,
differentiated keratinocytes require about two weeks to exit the nucleated
compartment and an additional two weeks to move through the stratum corneum.
The basement membrane zone represents the junction between the epidermis and
the dermis. Additional cell populations that reside within the epidermis
include melanocytes along the basal layer, which supply melanin to the
surrounding keratinocytes via melanosomes, and Langerhans cells, which serve as
antigen-presenting cells. On the left lightly pigmented skin and on the right
is darkly pigmented skin.
Melanocytes are derived
from neural crest cells and primarily produce melanin, which is responsible for
the pigment of the skin. They are found between cells of stratum basale and
produce melanin. UVB light stimulates melanin secretion which is protective
against UV radiation, acting as a built-in sunscreen. Melanin is produced
during the conversion of tyrosine to DOPA by the enzyme tyrosinase. Melanin
then travels from cell to cell by a process that relies on the long processes
extending from the melanocytes to the neighboring epidermal cells. Melanin
granules from melanocytes are transferred via the long processes to the
cytoplasm of basal keratinocyte. Melanin transferred to neighboring
keratinocytes by “pigment donation”; involves phagocytosis of tips of
melanocyte processes by keratinocytes.
Members of the third
major resident epidermal population, Langerhans cells,
have the capacity to metabolize complex antigenic materials into peptides, some
of which are immunogenic. Langerhans cells, dendritic cells, are the
skins first line defenders and play a significant role in antigen presentation.
These cells need special stains to visualize, primarily found in the stratum
spinosum. These cells are the mesenchymal origin, derived from CD34 positive
stem cells of bone marrow and are part of the mononuclear phagocytic system.
They contain Birbeck granules, tennis racket shaped cytoplasmic organelles.
These cells express both MHC I and MHC II molecules. After
activation, these cells traffic out of the epidermis toward regional lymph
nodes, where they play a critical role in antigen presentation during the
induction and regulation of immunity.
Merkel cells, which contain neuroendocrine peptides within
intracytoplasmic granules, are oval-shaped modified
epidermal cells found in stratum basale, directly above the basement membrane.
These cells serve a sensory function as mechanoreceptors for light touch, and
are most populous in fingertips, though also found in the palms, soles, oral,
and genital mucosa. They are bound to adjoining keratinocytes by desmosomes and
contain intermediate keratin filaments and their membranes interact with free
nerve endings in the skin.
The most obvious
function of epidermis lies in the stratum corneum, the semipermeable laminated
surface aggregate of differentiated (keratinized) squamous epithelial cells,
which serve as a physiologic barrier to chemical penetration and microbiologic
invasion from the environment, as well as a barrier to fluid and solute loss
from within.
Dermis
Beneath the epidermis, a
vascularized dermis provides structural and nutritional support. The dermis is connected to the epidermis at the level of the
basement membrane and consists of two layers, of connective tissue, the
papillary and reticular layers which merge together without clear demarcation.
The papillary layer is the upper layer, thinner, composed of
loose connective tissue and contacts epidermis. The reticular layer is
the deeper layer, thicker, less cellular, and consists of dense connective
tissue/ bundles of collagen fibers. The dermis houses the sweat glands, hair,
hair follicles, muscles, sensory neurons, and blood vessels.
Dermis is composed of a
glycosaminoglycan gel held together by a collagen- and elastin-containing
fibrous matrix. Vascular structures, accompanied by nerves and mast cells,
course through the dermis to provide nutrition, recirculating cells, and
cutaneous sensation. Three additional cells, fibroblasts, macrophages and
dermal dendritic cells complete the list of dermal residents. In pathologic
conditions such as acute inflammation, the functions and types of dermal cells
change substantially, with a variety of infiltrating leukocytes arriving via
vascular routes. In fact, the composition of cutaneous infiltrates differs
depending on the disease entity, which provides useful diagnostic clues.
The extracellular matrix of the dermis is
composed of structural proteins (collagen, elastin) and a gel-like ground
substance (glycosaminoglycans). There are also blood vessels that supply
nutrition and recirculating cells, lymphatic vessels, and nerve fibers. Adnexal
structures are also present, with variations depending upon body site. Other cell
types present in the dermis include mast cells, fibroblasts, macrophages, and
dermal dendritic cells.
Epidermal basement membrane
·
Basement membranes serve as: (1) a substrate for attachment of
cells; (2) a template for tissue repair; (3) a matrix for cell migration; (4) a
substratum to influence differentiation, morphogenesis, and apoptosis of
epithelial cell layers; and (5) a permeability barrier for cells and
macromolecules
·
By transmission electron microscopy, the major ultrastructural
sub regions (from superior to inferior) of the epidermal basement membrane are:
(1) the cytoskeleton, hemidesmosomal plaques, and plasma membranes of basal
keratinocytes; (2) an electron-lucent region termed the lamina lucida; (3) the
lamina densa; and (4) the sublamina densa region of the papillary dermis
·
In the “laminated” model of the epidermal basement membrane,
keratin intermediate filaments within basal keratinocytes attach to small (i.e.
<0.5 microns), electron-dense units (hemidesmosomes) on the basal plasma
membranes of these cells. In turn, anchoring filaments (small thread-like
strands) connect hemidesmosomes to the lamina densa. The lamina densa is
tethered to the dermis by anchoring fibrils, units that by originating and
ending in the underside of the lamina densa create ultrastructural loops that
serve as attachment sites for fibrillar proteins in the papillary dermis
·
Acquired or inherited abnormalities in structural proteins
within the epidermal basement membrane often result in a disease phenotype
characterized by blister formation
Four major ultrastructural
subregions of the epidermal basement membrane.
The
major ultrastructural subregions of the epidermal basement membrane consist of
the following: (1) cytoskeleton, hemidesmosomal plaques and plasma membranes of
basal keratinocytes; (2) electron-lucent lamina lucida; (3) lamina densa; and
(4) sublamina densa region of the papillary dermis.
“Laminated” model of the
epidermal basement membrane.
In
the laminated model, keratin intermediate filaments attach to electron-dense
hemidesmosomes on the basal plasma membranes of keratinocytes. Hemidesmosomes
connect to the underlying lamina densa (basement membrane proper) by small
thread-like strands termed anchoring filaments. The lamina densa and the
overlying epidermis are tethered to the papillary dermis by anchoring fibrils,
a series of looping elements along the underside of the lamina densa that serve
as attachment sites for fibrillar proteins in the papillary dermis.
Subcutaneous fat
The Subcutaneous
fat is deep to the dermis and is
also called hypodermis. It is the deepest layer of skin and contains adipose
lobules along with some skin appendages like the hair follicles, sensory
neurons, and blood vessels. Fat is a major component of the human body
and approximately 80% of fat is in the subcutis; the rest surrounds internal
organs. In non‐obese
males, 10–12% of body weight is fat, while in females the figure is 15–20%. Fat
comprises white and brown adipose tissue. The function of fat is to provide
insulation, mechanical cushioning and an energy store. In addition, fat may
have an endocrine function, communicating with the hypothalamus via secreted
molecules such as leptin to alter energy turnover in the body and to regulate
appetite. Adipocytes also have important signalling roles in osteogenesis and
angiogenesis, and additional physical functions such as phagocytosis.
Multipotent stem cells have been identified in human fat, which are capable of
developing into adipocytes, osteoblasts, myoblasts and chondroblasts.
FUNCTIONS OF THE SKIN
The skin is the site of many complex and dynamic processes
as demonstrated in Figure and Table. These processes include barrier and
immunologic functions, melanin production, vitamin D synthesis, sensation,
temperature regulation, protection from trauma and aesthetics.
Figure:
Cross-section of skin.
Table: Structure and function of the skin
BARRIER FUNCTION
The epidermal barrier protects the skin from microbes,
chemicals, physical trauma, and desiccation due to transepidermal water
loss. This barrier is created by
differentiation of keratinocytes as they move from the basal cell layer to the
stratum corneum. The keratinocytes of the epidermis are produced and renewed by
stem cells in the basal layer resulting in replacement of the epidermis
approximately every 28 days. It takes 14 days for these cells to reach the
stratum corneum and another 14 days for the cells to desquamate. Keratinocytes
produce keratins, structural proteins that form filaments that are part of the
keratinocyte cytoskeleton. In the stratum spinosum keratin filaments radiate
outwards from the nucleus and connect with desmosomes which are prominent under
the microscope giving a “spiny” appearance to cells. As cells move into the
stratum granulosum, keratohyalin granules composed of keratin and
profilaggrinare formed. Profilaggrin is converted into filaggrin (filament
aggegation protein) that aggregates and aligns keratin filaments into tightly
compressed parallel bundles that form the matrix for the cells of the stratum
corneum. Filaggrin gene mutations are associated with ichthyosis vulgaris and
atopic dermatitis. As keratinocytes move into the stratum corneum they lose
their nuclei and organelles and develop a flat hexagon shape. These cells are
stacked into a “bricks and mortar”–like pattern with 15 to 25 layers of cells
(bricks) surrounded by lipids (mortar). The lipids consist of ceramides, free
fatty acids, and cholesterol.
IMMUNOLOGIC FUNCTION
Epithelial cells at the interface between the skin and
the environment provide the first line of defense via the innate immune
system. Epithelial cells are equipped to
respond to the environment through a variety of structures including Toll-like
receptors (TLRs) of which there are at least 10, nucleotide-binding
oligomerization domain-like receptors, C-type lectins, and peptidoglycan
recognition proteins. TLR-mediated activation of epithelial cells is also
associated with the production of defensins and cathelicidins, families of
antimicrobial peptides.
Dendritic cells bridge the gap between the innate and
adaptive immune systems. Dermal dendritic cells can induce auto proliferation of
T cells and production of cytokines as well as nitric oxide synthase. The exact
function of dendritic epidermal Langerhans cells is an area of rapidly evolving
research suggesting that these cells are very important to the modulation of
the adaptive immune response.
MELANIN PRODUCTION AND PROTECTION FROM ULTRAVIOLET LIGHT DAMAGE
Melanocytes comprise 10% of the cells in the basal cell
layer. There is another population of melanocytes in the hair follicle that is
responsible for hair color and replacing epidermal melanocytes as needed.
Melanocytes produce melanin, a pigmented polymer that absorbs UV light. Melanin
is synthesized from tyrosine in several steps that require the enzyme
tyrosinase. As melanin is produced it is then packaged into melanosomes, a
specialized organelle. Melanosomes are phagocytosed by keratinocytes and moved
to an area above the keratinocyte’s nucleus acting as a protective shield from
UV light. One melanocyte provides melanosomes for as many 30 to 40
keratinocytes. All humans have the same number of melanocytes. The variation in
the degree of skin color is due to variations in melanosomes. Individuals with
darker brown skin tones have more abundant, larger, and more dispersed
melanosomes. Exposure to UV light stimulates the production of melanin within
melanosomes producing a “tan.” Tyrosinase deficiency is associated with
albinism and vitiligo is associated with absence of melanocytes.
SYNTHESIS OF VITAMIN D
The main sources for vitamin D are dietary intake and
production of vitamin D precursors by the skin. With exposure to UV light
provitamin D 3 (7-dehydrocholesterol) in the epidermis is converted into
previtamin D that converts into vitamin D 3. Vitamin D 3 is converted to its metabolically
active form in the liver and kidneys.
SENSATION
The skin is one of the principal sites of interaction
with the environment and many types of stimuli are processed by the peripheral
and central nervous systems. Initially, cutaneous nerves were classified as
being either “afferent” controlling sweat gland function and blood flow or
“efferent” transmitting sensory signals to the central nervous system, but
after the discovery of the neuropeptide substance P (SP) and other
neuropeptides in sensory nerves, many trophic properties of nerve fibers and
neuropeptides have been reported.
There are 3 major nerve types in the skin:
• Aβ fibers—large, heavily myelinated nerve fibers that
transmit tactile sensation
• Aδ fibers—thinly myelinated nerve fibers involved in
the transmission of short and fast painful stimuli
• C-fibers—unmyelinated nerves that transmit pain and
itch sensations
Mixed nerve fiber bundles form a plexus from which
individual nerve fibers extend toward their specific targets. The first tier is
underneath the epidermis and innervates the epidermis and cutaneous
mechanoreceptors or the upper dermis.
The second and third tiers are located between the dermis
and subcutis or in the deep subcutis and innervate hair follicles, the arrector
pili muscles, and sweat glands as well as the lower dermis and subcutis. All 3
plexi innervate blood vessels, smooth muscle cells, and mast cells, thereby
connecting different skin cell populations with the brain.
TEMPERATURE REGULATION
The skin helps to regulate and maintain core body
temperature through regulation of sweating and varying the blood flow in the
skin. Evaporation of sweat contributes to temperature control of the body.
Under normal conditions 900 mL of sweat is produced daily. With increased
physical activity or increased environmental temperature, 1.4 to 3 L of sweat
per hour can be produced. The regulation of blood flow in the capillaries in
the dermal papillae and other cutaneous vessels plays an important role in
convective heat loss and heat conservation. Normally the blood flow in the skin
is approximately 5% of the cardiac output, but in extremely cold temperatures
it can drop to almost zero and in severe heat stress it can be as high as 60%.
Dysfunction of thermoregulation can lead to hyperthermia and hypothermia.
PROTECTION FROM TRAUMA
The dermis varies in thickness from 1 to 4 mm. It
protects and cushions underlying structures from injury and provides support
for blood vessels, nerves, and adnexal structures. It is separated from the
epidermis by the basement membrane, which is created by the basal layer of the
epidermis. Collagen is responsible for the tensile strength of the skin and
comprises 75% of the dry weight of the dermis. Defects in collagen synthesis
are associated with diseases such as Ehlers–Danlos syndrome (hyperextensible
joints and skin). Elastic fibers are responsible for the elasticity and
resilience of the skin and are 2% to 3% of the dry weight of the skin. Defects
in elastic fibrils can be associated with cutis laxa and Marfan syndrome.
IDENTITY AND AESTHETICS
The perception of an individual’s ethnicity, age, state
of health, and attractiveness is affected by the appearance of his or her skin
and hair. Sun-damaged skin, rashes, hair disorders, pigment disorders, and acne
can have a profound effect on how individuals perceive themselves and others.
Embryology
The epidermis is derived from ectodermal tissue.
The dermis and hypodermis are derived from mesodermal tissue
from somites. The mesoderm is also responsible for the formation of Langerhans
cells. Neural crest cells, responsible for specialized sensory nerve endings
and melanocyte formation migrate into the epidermis during epidermal
development.
Blood Supply and Lymphatics
Blood vessels and lymphatic vessels are found in the dermal layer
of the skin. Blood supply to the skin is an arrangement of two plexuses, the
first lies between the papillary and reticular layers of the dermis and the
second lie between the dermis and subcutaneous tissues. Supply to the epidermis
is by way of the superficial arteriovenous plexus (subepidermal/papillary
plexus). These vessels are important for temperature regulation. The mechanism
by which the body regulates temperature through the skin is very effective and
works by increased blood flow to the skin, transferring heat from the body
to the environment. The changes in blood flow are controlled by the autonomic
nervous system, sympathetic stimulation resulting in vasoconstriction (heat
retention) and while vasodilation results in heat loss. Vasodilation of the
blood vessels is the response to increased body temperature and is the result
of inhibition of the sympathetic centers in the posterior hypothalamus whereas
decreased body temperature will cause vasoconstriction of skin blood
vessels.
Nerves
Nerves of the skin include both somatic and autonomic nerves. The
somatic sensory system is responsible for pain (nociceptors), temperature,
light touch, discriminative touch, vibration, pressure, and proprioception
medicated primarily by specialized cutaneous receptors/end organs including
Merkel disks, Pacinian corpuscles, Meissner’s corpuscles, and Ruffini
corpuscles. The autonomic innervation is responsible for the control of the tone
of the vasculature, pilomotor stimulation at the hair root, and sweating.
The free nerve endings extend into the epidermis and sense
pain, heat, and cold. They are most numerous in the stratum granulosum layer
and surround most hair follicles. Merkel disks sense light touch and reach the
stratum basale layer. The other nerve endings are found in the deeper portions
of the skin and include the Pacinian corpuscle which senses deep pressure,
Meissner’s corpuscle which senses low-frequency stimulation at the level of the
dermal papillae, and Ruffini corpuscles which sense pressure.
Muscles
The arrector pili muscles are bundles of smooth muscle fibers that
attach to the connective tissue sheath of hair follicles. When the muscles
contract, they pull the hair follicle outward resulting in the hair erecting up
but also compresses the sebaceous glands, resulting in the secretion of their
contents. Hair does not exit perpendicularly, but instead at an angle. This
erection of hair also produces goosebumps, the bumpy appearance of the
skin.
Physiologic Variants
Skin is continuously shedding and desquamating and varies slightly
depending on the body region. There are more layers of cells in thicker
hairless skin with an additional layer, known as the stratum lucidum. Overall,
the process of cell division, desquamation, and shedding go as follows:
1.
Cell division occurs in stratum basale/germinativum. One cell
remains, another cell is pushed toward the surface. Basal cells
begin synthesis of tonofilaments (composed of keratin) which are grouped
into bundles (tonofibrils).
2.
Cells are pushed into stratum spinosum. In the upper part of the
spinous layer, cells begin to produce keratohyalin granules having
intermediate-associated proteins, filaggrin, and trichohyalin; helps aggregate
keratin filaments and conversion of granular cells to cornified cells, i.e.
keratinization. Cells also produce lamellar bodies.
3.
Cells are pushed into stratum granulosum and become flattened and
diamond shaped. The cells accumulate keratohyalin granules mixed between
tonofibrils.
4.
Cells continue to stratum corneum where they flatten and lose
organelles and nuclei. The keratohyalin granules turn tonofibrils into a
homogenous keratin matrix.
5.
Finally, cornified cells reach the surface and are desquamated via
a break-down of desmosomes. Proteinase activity of KLK (kallikrein-related
serine peptidase) is triggered by lowered pH near the surface.
