Integumentary Tissue

The integumentary system is a tough system that covers the whole body. It consists of the skin and its appendages, which include the hair, sweat glands, the sebaceous glands and nails.

The Skin

The skin is the largest organ in the body; it constitutes about 16% of the body weight. It consists of the epidermis and dermis and overlies the hypodermis (subcutis) which is usually a connective adipose tissue of variable thickness and appearance. The skin contains specialized appendages that include hair follicles, sweat glands, sebaceous glands and nails.

The epidermis develops from the embryonic ectoderm whereas the dermis develops from the mesoderm, specifically from the somite dermatomes. The skin has many functions, which include protection, thermoregulation, sensation and vitamin D synthesis. It provides a protective barrier against mechanical, thermal and physical injury and hazardous substances. It reduces harmful effects of UV radiation and prevents loss of moisture. It acts as a sensory organ sensing touch, heat and pain. It also has an immunological role in detecting infectious agents that cross the epidermal mechanical barrier and plays an important role in body temperature regulation.

Fig. O1. An H&E-stained histological section showing the general features of the skin, skin appendages and the hypodermis.

Types of Skin

There are two types of skin: thick skin and thin skin. Thick skin is hairless and is found in palms of the hands and soles of feet. It is thick in the sense that it has a thick epidermis. Thin skin is hairy and found elsewhere; it has a thinner epidermis.

Fig. O2. H&E- and trichrome-stained sections showing the general structures of hairless skin (left) and hairy skin (right).

Histology of the Skin

The skin has two histologically different components, the epidermis and the dermis.

The Epidermis

The epidermis is a typical epithelium, and accordingly is totally devoid of blood vessels. The underlying dermis and hypodermis are the source of all nutrients for cells of the epidermis.

As with other epithelial sheets, the regenerative capacity of the epidermis is high. Rapid and continuous production of new epidermal cells in the deep layers of the epidermis is needed to keep up with the constant wearing and loss of epidermal cells on the surface. A typical human being loses as much as 250 grams of skin a day. Epidermal cells are flaked off at the surface and renewed by mitosis in the deep layers of the epidermis. 

Fig, O3. H&E-stained histological sections showing the general features of the epidermis and its relation to the dermis.

Keratinocytes

There is a continuous turn of over of cell in the epidermis. New epidermal cells are produced by mitosis in the basal layer of the epidermis are pushed towards the surface. As they move upwards the cells mature and produce keratin; they are thus known as keratinocytes. The process of mitosis, upwards movement of keratinocytes and their maturation is known as keratinogenesis. Keratinogenesis is the reason why the epidermis shows clearly visible layers. These layers are: the stratum basale, stratum spinosum, stratum granulosum, stratum lucidum and stratum corneum.

Fig, O4. The illustration shows four non-keratinocytes among an overwhelming majority of keratinocytes, which proliferation, differentiation, migration upwards and degradation form the different strata of the epidermis.

The vast majority of epidermal cells (>95%) are keratinocytes. Keratinocytes are keratin. producing cells. Keratinocytes are continuously produced by mitosis in the basal layer. newly formed cells are pushed towards the surface where they die and are desquamated. Lost cells are replaced by new cells produced by mitosis carried out by the basal cells of the epidermis. The life of keratinocytes - from production to sloughing off is 25 - 50 days. keratinocytes in the middle and basal parts of the epidermis are viable, dividing cells. They then differentiate, mature and end up as flattened dead sacs full of a protein called keratin. he different layers of the epidermis represent well-defined stages of the keratinocytes’ life history.

Stratum Basale 

The stratum basale is also known the stratum cylindricum because it a single layer of high cuboidal or columnar cells that look like cylinders. It is the deepest layer of the epidermis and is made of a single layer of unipotential keratinocyte progenitor cells oriented vertically upon the basal lamina. Almost all the proliferative activity of epidermal cells occurs in this layer. Any chemical or physical agent that interferes with cell division in this layer results in sloughing of the skin because the replacement cycle is hampered. Cytotoxic drugs used in cancer therapy have a similar effect, because they target rapidly proliferating cells.

Stratum Spinosum

This layer is also known as the prickle cell layer.  It is located above the stratum basale. Its cells can divide, but only when there is high demand for new cells. For this reason, the stratum spinosum and the stratum basale are together called the stratum germinativum. The stratum spinosum is characterized by the presence of numerous hair-like spines in between adjacent cells, forming what are known as the intercellular bridges. The Intercellular bridges are the sites where the adjacent spinosum cells are firmly held together by desmosomes, which are seen only by the electron microscope. The bridges are artifacts that result from shrinkage of cells during tissue processing with their points attachment at desmosomes remaining intact. Desmosomes are anchored to the cytoplasm of keratinocytes by tonofilaments. Keratinocytes of the stratum spinosum are active in the synthesis of cytokeratin, a water-repelling protein that helps prevent water loss. Cytokeratin is in the form of filaments that aggregate to form tonofibrils. Tonofilaments attach to desmosomes and strengthen the anchorage of keratinocytes to each other.

Fig. O5. The histological section on the left is from the lower and middle parts of the epidermis showing both the stratum basale and the stratum spinosum. The histological section on the right is from the stratum spinosum showing clear intercellular spaces spanned by intercellular bridges.

Fig. O6. The illustration on the left shows how intercellular bridges are formed due to shrinkage of the spinosum cells (during tissue processing). The electron micrograph on the right shows the ultrastructure of desmosomes (two dark broad lines) joining adjacent keratinocyte. The darks thread-like structures are tonofilaments.

Stratum Granulosum

This layer is characterized by the presence of keratohyaline granules in the cytoplasm of its keratinocytes. Keratohyaline granules are basophilic and contain lamellar prekeratin. Keratinocytes of this layer are terminally differentiated cells; they cannot divide. The stratum granulosum is prominent in thick skin; in thin skin, it is attenuated or even altogether absent. The cytoplasm of keratinocytes of this layer contains prominent tonofibrils. However, these fibrils are obscured by the keratohyaline granules that are full of keratin, which is a fibrous protein. Cells die in this layer due to rupture of lysosomes.

Fig. O7. Two H&E-stained histological sections of the epidermis. The one on the left shows the low magnification appearance of the stratum granulosum, whereas the one on the right is a higher magnification that shows the basophilic cytoplasmic keratohyalin granules.

Stratum Lucidum

Stratum lucidum is found only in thick skin; it is not found in thin skin. It is a homogenous translucent layer made of lifeless bags, made of cell membranes and filled with a fibrous protein called eleidin. Eleidin is a transparent intermediate form of keratin rich in lipids. It is a form of protein transitional between that present in keratohyaline granules and the fully mature keratin fibers present in the stratum corneum. The red colour of lip is related to abundance of eleidin in its epidermis. This sharp demarcation line between the lip and the adjacent skin is called the vermillion (vermilion) border.

Stratum Corneum

The corneum is also known as the horny layer. It is the superficial layer of the epidermis. It is made of flattened dead cells devoid of nuclei. It appears markedly eosinophilic in H&E sections due to the presence of large amounts of keratin in it. Keratin is a protein, and proteins are acidophilic. Desmosomes hold the dead cells together in the deeper parts of this layer but are lost in the superficial parts. The loss of desmosomes in the superficial parts of stratum corneum leads to separation of the dead cells from each other and accordingly it is called the stratum disjunctum. Separated dead cells are ultimately lost from the surface by desquamation (sloughing off).

Fig. O8. The trichrome-stained section on the left shows the general histological features of thick skin. The H&E-stained section on the right shows the stratum lucidum and the stratum corneum. The stratum lucidum is homogeneous and pale and the stratum corneum id deeply eosinophilic.

Non-keratinocytes

In addition to keratinocytes, the epidermis contains other types of cells known as non-keratinocytes. Non-keratinocytes are comparatively few. They constitute about 5% of cells of the epidermal cells. Non-keratinocytes are of three types:

1.      Melanocytes

2.      Langerhans cells

3.      Merkel cells

Melanocytes

Melanocytes are derived from the embryonic neural crest; they are thus of ectodermal origin. In H&E-stained histological sections, they appear as pale cells with spherical nuclei located in the basal layer of the epidermis. Therefore, they are difficult to identify in H&E sections. They are better demonstrated by special stains such as Fontana-Masson staining method or by immunohistochemistry. The cell bodies of melanocytes are confined to the basal layer of the epidermis, but their numerous long branching processes extend upwards in-between keratinocytes of the overlying stratum spinosum. Melanocytes produce melanin, which is a common biological pigment. Melanin gives the skin its colour and protects against UV light. It is synthesized by rER, packed by Golgi and stored within unique cytoplasmic organelles called melanosomes. Melanin from the melanosomes is transferred to the keratinocytes surrounding melanocytes and their processes.

Fig. O9. The histological sections on the left show melanocytes in the basal layer of the epidermis. In the H&E-stained section (above), the melanocytes show a pale cytoplasm whereas immunohistochemistry (below) shows them as dark brown cells. The illustration of the right shows melanocyte processes climbing in between keratinocytes of the stratum spinosum passing melanin granules to them.

Langerhans Cells

Langerhans cells are present in the middle and upper parts of the stratum spinosum. They belong to the cells of the immune system. They are antigen presenting cells that pick-up antigens from the epidermis, migrate out of the epidermis as veiled cells to reach lymph nodes where they present the picked up antigens to T-lymphocytes. They are important participants in skin allergic responses. Langerhans cells seen as pale in H&E-stained histological sections, They are clearly demonstrated by specific immunohistochemical methods. Electron microscopy reveals as having characteristic tennis racket-like structures called Birbeck granules.

Fig. O10. The H&E-stained section (left) shows Langerhans cells as pale cells between the eosinophilic keratinocytes. The CD1a-stained section (middle) shows Langerhans cells are very dark brown cells with processes. The electron micrograph on the right shows Birbecks granules.

Merkel Cells

Merkel cells occur singly or in small groups within or near the stratum basale. They are comparatively numerous in highly sensitive places, such as the fingertips. They are associated with sensory nerve endings (tactile discs) with which they make synaptic junctions. They are mechanoreceptors that respond to light touch.

Fig. O11. The illustration on the left shows the epidermis containing a Langerhans cell (green), Merkel cell (blue) and approaching nerve fibers (red). The illustration on the right shows the close association between a Merkel cell and sensory nerve ending. 

The Dermis

Dermis is the connective tissue that underlies the epidermis. It is equivalent to the lamina propria of epithelial membranes. It is essentially made of collagen and elastic fibers, in additions to the different types of connective tissue cells. It contains blood vessels and lymphatic vessels and nerves, in addition to skin appendages including hair follicles and sweat glands. The dermis consists of two layers, namely the papillary layer and the reticular layer.

Fig. O12. An H&E-stained section and a trichome stained section of the skin showing the papillary dermis and the reticular dermis, the reticular dermis contains coarser bundles od collagen fibers.

Papillary Layer of the Dermis

The papillary layer is made of a loose connective tissue with comparatively few collagen and elastic fibers, and more connective tissue cells. The cells present in the dermal connective tissue include fibroblasts, macrophages (histiocytes) and adipocytes (fat cells). In addition, the dermis contains many small blood vessels, lymphatic vessels and nerve fibers. It also contains sensory nerve endings and receptor structures such as Meissner’s corpuscles. The superficial parts of the dermis project into the epidermis forming finger-like projection called dermal papillae, which strengthen the anchorage of the epidermis to the dermis.

Reticular Layer of the Dermis 

 This layer is thicker than the papillary layer. It is composed of a dense irregular connective tissue characterized by coarse bundles of collagen fibers passing in different directions giving this layer the appearance of a reticulum (net-like). Collagen fibers in this layer and also in the papillary layer, provide a tensile strength that holds tissues of the skin firmly together. In addition, collagen binds with water and keeps the skin hydrated (cosmetic collagen injection). Elastic fibers give elasticity to the skin. The reticular layer is well vascularized and has a rich sensory and sympathetic nerve supply.

Fig, O13. An H&E-stained section of the skin showing the papillary dermis making projections in the epidermis; these are called dermal papilla.

The Hypodermis

The Hypodermis is also known as the subcutis or the superficial fascia. It lies below the dermis and serves to connect the skin to the underlying fascia. The border between the hypodermis and dermis is often difficult to see. The hypodermis is a well-vascularized loose connective tissue, mixed up adipose tissue which serves as a storage of excess energy, insulation and cushioning for the skin. Sites of fat deposition within the hypodermis are hormone dependent, and dependent on the individual’s genetic makeup. The most important hormones in this respect are estrogen, testosterone, insulin, glucagon and leptin.

Fig. O14.  An H&E-stained section showing the skin and the hypodermis. The Hypdermis appears pale it contains numerous adipocytes. It also contains the deeper parts of the hair follicles. Fig. O14.  An H&E-stained section showing the skin and the hypodermis. The Hypdermis appears pale it contains numerous adipocytes. It also contains the deeper parts of the hair follicles. 

The Dermo-Epidermal Boundary

The epidermis is not a flat sheet. Its border with the underlying connective tissue of the dermis is an undulating and irregular lamina. The downward projections of epidermis are called epidermal pegs or rete ridges. They are matched to corresponding ridges of the dermis known as the dermal papillae thus forming an interlocking boundary.  This boundary firmly anchors the epidermis with the dermis. The degree of interdigitations (interlocking) is related to the level of wear. Areas with high levels of wear have lots of deep interdigitation, whereas those of low wear have fewer interdigitations. The interdigitations of dermal ridges and epidermal pegs is what makes the unique pattern of fingerprints. The dermo-epidermal boundary contains the epidermal basement membrane which consists of a homogenous basal lamina and fine fibrous proteins associated with the basal lamina. The basal lamina can only be seen with the electron microscope. The basement membrane can be seen with the light microscope in histological sections stained by special techniques such silver staining methods and the PAS technique. The basal cell layer keratinocytes are anchored to the basal lamina by hemidesmosomes.

Fig. O15.  The illustration on the left shows the three-dimensional appearance of dermo-epidermal junction after separating the epidermis from the dermis. The dermal papillae are showing as numerous finger-like projections. The electron micrograph on the right shows the basal lamina and keratinocytes attached to it by hemidesmosomes.

Skin Appendages

 There are several functional structures that are associated with the skin. These include the sweat glands, the hair, the sebaceous glands and the nail.

Fig. O16. The illustrations show the four types of skin appendages, namely the sweat glands, the hair, sebaceous glands and the nail.                            

Sweat Glands

Sweat glands are simple coiled tubular glands that produce sweat. They are distributed throughout the body. They are of two types:

1. Eccrine sweat glands

2. Apocrine sweat glands

Eccrine Sweat glands

These are also known as merocrine sweat glands. Eccrine sweat glands participate in regulation of the body temperature. They are distributed all over the body, except the lips, penis, clitoris and labia minora which lack sweat glands. Each gland consists of a duct and a secretory unit. The epithelium of the duct is bi-stratified cuboidal epithelium, whereas the epithelium of secretory unit is simple high cuboidal epithelium which contains two types of cells: large eosinophilic clear cells which secrete Na+, and small basophilic cells that produce glycoproteins. Eccrine sweat glands pass out their secretion by the merocrine mode of secretion i.e. by exocytosis without loss of any part of the secretory cells. Secretory vesicles containing sweat emerge from the Golgi complex and travel towards the cell membrane where they fuse with the cell membrane, then open releasing their content outside the cell. The activity eccrine glands are under the control of the autonomic nervous system. Myoepithelial cells are present around secretory cells; they contract and relax in response to the adrenergic and cholinergic endings present in the vicinity. Myoepithelial cells may also function as progenitor cells that play a role in the maintenance of the sweat glands.

Fig. O17.  The H&E-stained histological section (left) and the illustration (middle) show the sweat gland as a simple tubular coiled gland. The epithelium of the duct is a two-layered stratified cuboidal epithelium. The histological section (above left) and the illustration (below left) show the myoepithelial cells and the two types of secretory cells.

Apocrine glands

This type of sweat glands is confined to certain locations in the body, which include the axilla, around genitalia and nipples. Apocrine sweat glands are often associated with hair follicles. The secretory unit has one type of cell instead of two as in eccrine sweat glands. They contain eosinophilic cells only. They produce a milky secretion. Secretion of apocrine gland takes place by the apocrine mode of secretion, where the secretory vesicles accumulate in the apical part of the cell. The apical part of the secretory cell bulges out into the lumen of the secretory unit and is pinched off passing into the unit’s lumen as the secretory product. Accordingly, the secretory cells are high just prior to secretion and low immediately after.

Apocrine sweat glands start their function at puberty influenced by sex hormones. Secretion is expelled out the gland by myoepithelial cell contraction due to adrenergic stimulation. The secretion is odorless but becomes smelly due to the action of cutaneous bacteria. The ceruminous glands of the external ear, Moll glands of eyelids and the mammary glands are modified apocrine sweat glands.

Fig. O18. The illustration on the left shows the general features of apocrine sweat glands, the one in the middle demonstrates the apocrine mode of secretion. The H&E-stained section on the right shows myoepithelial cells around the secretory cells. The apical parts of some of the secretory cells is full of secretory granules and bulge out into the lumen in preparation for pinching off.

The Hair

The hair consists of

1. The hair shaft

2. Hair bulb and

3. Hair follicle

Hair Shaft

The hair shaft is a keratinized cylindrical structure made essentially of hard keratin. It has more disulfide cross-linkages than the soft keratin. It consists of an inner medulla and an outer cortex. The medulla is less keratinized than the cortex and is often absent in fine hair. The cortex is surrounded by the cuticle, which is thin and keratinized. The cuticle in turn is surrounded by two layers of epithelial cells called the internal and external root sheathe. The hair shaft is surrounded by the hair follicle, which is a tubular structure made of four layers.

Fig. O19. The illustration on the left shows the components of the hair and the one on the right shows its cross-sectional appearance.

The Hair Follicle and Hair Bulb

Hair follicles are deep invaginations of the epidermis. Their deep end expands forming the hair bulb. The follicle comprises an inner root sheath (IRS) and an outer root sheath (ORS). Both are made of epithelial cells. The outer root sheath is surrounded by a glassy membrane, which is a form of a basement membrane, then by the connective tissue sheath. The hair bulb contains the hair matrix (matrix cells) that gives rise to hair in a manner similar to formation of stratum corneum from stratum basale.  Melanocytes in the matrix give colour to the hair.  Gray hair results from loss of these melanocytes. Basally, the bulb shows an invagination that contains a CT core known as the dermal or hair papilla.

Fig. O20. The illustrations and the H&E-stained section show components of the hair follicle.   

Types of Hair

Hair follicles are longer, more numerous and have more sebaceous glands in the scalp than elsewhere. Hair follicles in pubic area and axilla are curved and more oblique. They have apocrine sweat glands associated with them. Body hair in children and females is soft and fine; it called villus hair. The terminal hair of men is coarser. Scalp hair of Mongol races is round in transverse sections, that of Europeans (curly hair) is oval, whereas that of Africans is indented or kidney shaped. Melanocytes in hair matrix give hair its colour.

Growth of Hair

Hair has growth cycles made of a growing phase (anagen), transition phase (catagen) and a resting phase (telogen). In the growing phase (anagen) the follicle is longer with a large bulb located deep in the hypodermis. In the resting phase (telogen) the follicle is shorter, and bulb is small and lacks a dermal papilla (club hair). The growth phase is long (2 or more years) in scalp hair; in other types of hair the growing phase is much shorter than the resting hair.

Fig. O21. The illustration shows the appearance of hair in the three phases of the hair cycle, anagen, catagen and telogen.

Sebaceous Glands

Sebaceous glands are found in the skin in most parts of the body. They are usually associated with hair follicles. They lie within the connective tissue sheath of the hair, and their short ducts open into the upper 1/3 of hair follicles. The internal root sheath is absent in the regions where sebaceous glands are present. Sebaceous glands are branched acinar holocrine glands that secrete sebum on to the cuticle. The secretory cells produce and stores sebum, become full of sebum, detach from the surrounding cells and pass into lumen to disintegrate forming the secretory material. Sebum contains abundant of triglycerides and fatty acids. It conditions the hair and acts as a hydrophobic barrier to the epidermis. Sebum secretion is partially controlled by sex hormones.

Fig. O22. An H&E-stained section and an illustration show the microscopic features of sebaceous glands the holocrine mode of secretion of sebum.  

Arrector Pili Muscle

The arrector pili muscle is a bundle of smooth muscle that extends obliquely upwards from the hair follicle just beneath the level of the sebaceous gland towards the papillary dermis. It contracts when stimulated by the associated sympathetic nerve endings. Its contraction erects the hair follicle and expels sebum. The hair follicle, sebaceous gland and arrector pili are collectively called the pilosebaceous unit.

Fig. O23. An H&E-stained section of the pilosebaceous unit made of hair follicle, sebaceous gland and the arrector pili muscle.

The Nail

The nail is one of the skin appendages. It is essentially a keratinized plate known as the nail plate. It rests on the nail bed of the fingertip which is covered by stratified squamous epithelium. The nail root (proximal end of the nail) and the nail bed extend towards the deep dermis of the interphalangeal joint. The skin fold overlying the nail root is highly keratinized. The epithelium underlying the nail root is called the nail matrix. Nail grows by proliferation of the matrix cells followed by keratinization.

The nail is ectodermal in origin and consists of compact translucent keratinized cells that protect the distal dorsal areas of fingers and toes. It comprises about 200 rows of well differentiated keratinocytes called onychocytes. The nail plate appears as a modified stratum corneum, it contains keratinized cells devoid of nuclei. It is transparent because it lacks nuclei. There is no stratum disjunctum, so onychocytes are not lost by desquamation.  The nail matrix yields nail and consists of a stratified squamous epithelium devoid of a stratum granulosum and characterized by long rete ridges. The nail has few melanocytes than as compared to the epidermis; most of the melanocytes being present in the nail matrix. Beneath the nail matrix a connective tissue matrical dermis.

Fig. O24. The illustration on the left shows the components of the nail, whereas the H&E-stained section on the right shows their histological features.

Blood Supply of the Skin

The skin has two vascular plexuses.  These are the superficial dermal plexus in the dermo-hypodermal boundary and the sub-papillary deep dermal plexus which lies just beneath the papillary, Blood vessels in the deeper parts of the hypodermis supply the superficial cutaneous plexus. Vessels from this plexus supply the deep dermis, hair follicles, sebaceous glands and sweat glands. The subpapillary layer supplies the superficial parts of the dermis. The dermal blood capillary are continuous capillaries, and the circulation is a closed one, Arteriovenous anastomoses are common in the dermis and participate in the skin thermoregulation. Numerous lymphatics drain the skin.

Fig. O25. The illustration shows the Superficial dermal and deep dermal vascular plexus and the lymphatic drainage of the dermis.  

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