Introduction and Key Concepts for the Integumentary System

The skin and its accessory structures form the integumentary system. The skin covers the entire surface of the body and is the largest organ of the body in terms of its weight and volume. The accessory structures of the skin include hair, nails, and three types of glands: sebaceous, eccrine sweat, and apocrine. The skin is composed of several types of tissues: epithelium, connective tissue, muscles, blood vessels, and nervous tissue. The functions of skin include (1) Protection: The skin serves as a barrier between the internal tissues and the outside world, preventing damage to the internal tissues by physical trauma, toxic chemicals, radiation, and sunlight. (2) Prevention of dehydration: The skin forms a waterproof barrier, which prevents the loss of body fluids. (3) Regulation of body temperature: Evaporation of sweat released onto the body surface by the eccrine glands as well as dilation of the capillary network and arteriovenous anastomoses (shunts) in the skin help to regulate body temperature. (4) Somatosensory function: Sensory receptors in the skin transduce physical energy in an individual’s surroundings into action potentials that are carried by peripheral nerves to the central nervous system where the sensations of touch, pressure, pain, warmth, cold, vibration, etc. are generated.

(5)Immunological function: The Langerhans cells and lymphocytes in the skin play roles in the cutaneous immune response.

(6)Production of vitamin D: Vitamin D, an essential vitamin, is synthesized from precursors in the skin under the effects of steroids and sunlight.

Layers of the Skin

The skin can be divided into two basic layers: epidermis and dermis. The epidermis is a maximally keratinized stratified squamous epithelium, which is composed of five named layers of cells called keratinocytes. (1) The stratum basale is the deepest layer of the epidermis and it borders the dermis. A single layer of cuboidal or tall cuboidal cells lies on the basement membrane. Many of these cells are stem cells that actively divide and give rise to the cells in the other four layers. The epidermal keratinocytes are renewed constantly, with the top layer of cells continually being shed and new cells from the stratum basale replacing them. It takes about 3 to 4 weeks for keratinocytes to finish their renewal cycle. In addition to the keratinocyte stem cells, two special types of cells, melanocytes and Merkel cells (Merkel disks), are found in the stratum basale. The melanocytes are melanin producing cells which are in contact with the keratinocytes that are located immediately above the stratum basale (Fig. 13-7A,B). The Merkel cells (Merkel cell neurite complexes or Merkel disks) are sensory receptor cells, which respond to continuous touch stimuli. (2) The stratum

spinosum contains polyhedral keratinocytes, which become more flattened in the superficial part of this layer. The plasma membrane of neighboring cells is connected by desmosomes

(macula adherens). Langerhans cells (modified macrophages) are an additional cell type often found in this layer. (3) The stratum granulosum contains keratinocytes, which are flattened cells with keratohyalin granules in their cytoplasm. These granules are basophilic in appearance in H&E stained sections (Fig. 13-3B). This layer is more prominent in the thick skin than in the thin skin. (4) The stratum lucidum is a thin layer that is only found in the thick skin. It contains a few layers of flattened cells, which are densely packed together and lie beneath the stratum corneum. Their nuclei become pycnotic as they begin to degenerate. (5) The stratum corneum is the most superficial layer, which contains numerous extremely flattened cells completely filled with keratin. These cells have no nuclei or organelles and are technically dead cells. The cells on the surface are continuously shed. The dermis is a connective tissue layer deep to the epidermis. It contains the blood vessels, nerves, and afferent sensory receptors, including Meissner corpuscles and free nerve endings. The hypodermis is a transition (subcutaneous) layer below the dermis of the skin, which contains loose connective tissue, adipose tissue, nerves, arteries, and veins (Figs. 13-2 and 13-4A).

Thick Skin Versus Thin Skin

Thick skin is found in only a few places in the body, such as the palms of the hands and soles of the feet. It has a very thick epidermis. The stratum corneum is particularly prominent, being about 10 times thicker than that of thin skin. Thick skin has numerous eccrine sweat glands, but has no sebaceous glands or apocrine sweat glands. In contrast, thin skin, which covers the rest of the body, has a thin epidermis and its stratum corneum is much thinner than that of thick skin. The epidermis of thin skin consists of only four layers; the stratum lucidum is lacking in thin skin. Thin skin contains all three types of glands (Fig. 13-9A–C).

Accessory Structures of the Skin

Accessory structures of the skin include glands, hair, and nails:

(1) The glands of the skin include sebaceous glands, eccrine sweat glands, and apocrine sweat glands (Fig. 13-9A–C). The sebaceous glands secrete into hair follicles to keep the skin soft and moist and serve as a barrier to protect the skin. The eccrine sweat glands are important in regulating body temperature; they are found in both the thin and thick skin. The apocrine sweat glands are also called sexual scent glands; their function in humans is not clear. They may be involved in thermoregulation and are found only in some special regions of thin skin, such

as the axilla, nipple, and perianal and genital areas. (2) Hair is found in thin skin: the scalp, pubic region, and armpit (axilla) in adults have more abundant thick hair than other surfaces of the skin on the body. Hair growth is discontinuous and is controlled by various hormones. The hair follicles produce and maintain hair growth. The cycles of hair growth include three stages (from early to late): the anagen phase (active growth stage, lasting 2–6 years), the catagen phase (regression phase, lasting about 3 weeks), and the telogen phase (resting stage, lasting about 3 months). The hair shaft is shed as the follicle goes through the growth cycle and a new hair replaces it. In cross section, a hair follicle looks rather like an onion, with several rings or layers. The central part is the hair shaft, which has a scaly surface called the cuticle. The hair shaft is surrounded by an inner root sheath (with its own cuticle) and outer root sheath. The outer root sheath is covered by a connective tissue sheath (Fig. 13-10A). The deep end of the hair follicle is expanded into the hair bulb, which is composed of a dermal papilla (hair papilla) and a hair root composed mostly of the

hair matrix. The hair matrix is capable of cell division and gives rise to the hair shaft (Fig. 13-10B). (3) The nail is a translucent keratinized hard plate resting on the dorsum of the tip of each digit. The nail plate stems from the base of the nail (nail matrix) and grows over the nail bed toward the tip of the finger or toe. The components of the nail include the nail root (nail matrix), nail plate, the eponychium (nail cuticle), perionychium (nail wall), and hyponychium (Fig. 13-11A,B).

Development of the Skin

The skin develops from ectoderm and mesoderm. The epithelial cells of the epidermis are ectodermal derivatives, whereas Langerhans cells, the dermis (connective tissue), and subcutis (hypodermis) develop from the mesoderm. Melanocytes and Merkel cells originate from the neural crest. The basal cells of the epidermis give rise to the accessory structures (hair follicles, nails, and glands) of the skin (Fig. 13-12A,B).

Epidermis

Papillary layer

Dermis

Reticular layer

Hypodermis (subcutaneous layer)

5.Stratum corneum

4.Stratum

lucidum

3. Stratum Epidermis granulosum

2.Stratum spinosum

1.Stratum basale

Dermis

Figure 13-2. Overview of the layers of the epidermis.

Vein

Artery

Nerve

Horny cell (dead cell)

Flattened keratinocyte

Keratinocyte with keratohyalin granules

Langerhans cell

Keratinocyte

Merkel cell (Merkel disk)

Sensory nervous fiber

Small blood vessels

Papillary layer

Dermis

Reticular layer

Figure 13-3A. Thick skin, palm. H&E, 34; inset 116

The skin can be classified into thick skin and thin skin based on the thickness of the epidermis. Thick skin has a thick epidermis (400–600 μm) with five distinct cell layers. The stratum corneum is extremely thick in this skin. Thick skin covers the palms of the hands and soles of the feet. Thick skin has abundant eccrine sweat glands and lacks hair follicles. The epidermis is a stratified squamous epithelium. Because it is an avascular tissue (no direct blood supply), nutrients are delivered to the tissue by fluid diffusion from the dermis (connective tissue). The dermis is composed of a superficial papillary layer, a layer of loose connective tissue, and a deeper reticular layer, which is a thick layer of dense irregular connective tissue. This section shows thick epidermis containing the duct of an eccrine sweat gland.

Figure 13-3B. Layers of the epidermis, palm. H&E, 68; insets 422

The epidermis of thick skin has five layers. (1) The stratum basale contains a single layer of cuboidal/tall cuboidal cells (stem cells) and sits upon the basement membrane. This layer forms a dividing line between the epidermis and dermis (dotted line). (2) The stratum spinosum contains 5 to 10 layers of polyhedral keratinocytes, flattened toward the surface. These cells are also called prickle cells. (3) The stratum granulosum contains three to five layers of flattened keratinocytes filled with keratohyaline granules, which appear dark blue here. (4) The stratum lucidum is a very thin layer containing extremely flattened and tightly packed keratinocytes filled with keratin filaments. Their nuclei are beginning to be eliminated. (5) The stratum corneum is a layer of dead, nonnucleated cells, which form the most superficial layer of the skin. Cells in this layer are constantly sloughed off and replaced by new cells.

C

Dermal papilla

Meissner corpuscles

Epidermal

rete ridge

Figure 13-3C. Dermal papilla, palm. H&E, 272; inset

192

The border between the epidermis and dermis (dotted white line) is expanded into folds. The dermis is a connective tissue layer, which contains blood vessels, nerves, and sensory receptors (free nerve endings and Meissner corpuscles). The portion of the epidermis that projects into the dermis is termed the epidermal rete ridge, and the portion of the dermis that projects into the epidermis is called the dermal papilla. This unique feature increases the contact area between these two layers, preventing the epidermis from detaching from the dermis. The dermal papilla contains loose connective tissue that includes many capillaries, free nerve endings, and encapsulated sensory receptors. Meissner corpuscles are shown here. The nerve fibers cannot be seen in H&E stains; demonstration of nerve fibers requires special stains (Fig. 13-1; see also Chapter 7, “Nervous Tissue,” Fig. 7-8A,B). Meissner corpuscles are responsible for discriminative touch and are more numerous in thick skin such as at the tips of the fingers. These receptors help us to distinguish between, for example, different coins by touch alone.

Thin Skin

Figure 13-4A. Thin skin, scalp. H&E, 25; inset 84

Thin skin covers the entire body surface except for the palms of the hands and the soles of the feet. Thin skin has a thin epidermis, largely because its stratum corneum is much reduced compared to that of thick skin. In contrast to thick skin, thin skin contains hair follicles and their associated sebaceous glands. This section shows the epidermis and dermis of the skin and a deeper layer of subcutaneous tissue called the hypodermis. The hypodermis is a layer of loose connective tissue, which contains adipose tissue, nerves, arteries, and veins. The nerves give off branches, which provide the various types of sensory and autonomic nerve endings in the dermis. Pacinian corpuscles, sensory receptors that respond to vibration stimuli, are found in the hypodermis of both thin and thick skin. They are found in many regions of the body but are more numerous in the tips of the fingers and toes than in other areas (Fig. 13-1). The hypodermis serves as a transition layer, providing the dermis with a flexible attachment to the underlying muscles and other structures.

Figure 13-4B. Thin skin. Elastic fiber stain, 142; inset 487

The epidermis of thin skin consists of four layers, including the stratum basale, stratum spinosum, stratum granulosum, and stratum corneum. (The stratum lucidum is absent in thin skin.) The stratum granulosum is very thin, often only a single cell layer, and it is not easily distinguished in thin skin. The stratum corneum is thin but varies in thickness from region to region. This section is stained with an elastic fiber stain, which shows the elastic fibers in the dermis. These fibers become very fine toward the epidermis. The dermis contains type I collagen fibers and elastic fibers, which give the skin flexibility and strength. The inset shows a few very fine fibers called oxytalan fibers. The elastic fibers can be classified into three types based on their microfibril and elastin content: (1) elastic fibers, the largest fibers, containing predominantly elastin; (2) elaunin fibers, intermediate in size, containing small amounts of amorphous elastin; and (3) oxytalan fibers, the smallest fibers, containing only microfibrils.

Figure 13-4C. Stratum corneum, thin skin. Elastic fiber stain, 284

Fine grooves (sulci cutis) and elevated areas (cristae cutis) are the basis of the varying surface contours characteristic of specific areas of both thin skin and thick skin. The orientation of the grooves varies from region to region. Fingerprints (dermatoglyphics) are a good example of a skin pattern, which is distinctive. The top layer of the epidermis, the stratum corneum, is composed of several layers of flattened and cornified keratinocytes. These cells have no nuclei and are filled with keratin, which helps to stabilize the cells against physical stress. This layer of cells is constantly sloughed off and replaced by differentiating cells from beneath. In this section, the extensive spaces between the dead cells of the stratum corneum are artifacts of specimen preparation. Some of the cuboidal cells in the stratum basale are stem cells capable of cell division. Some cells derived by division of the stem cells remain in the stratum basale as stem cells and some begin differentiation in the stratum spinosum. Keratinocytes undergo an orderly sequence of differentiation (keratinization) and cell death (apoptosis) as they move up toward the surface of the epidermis.

CLINICAL CORRELATION

B

Eosinophilic squamous cell carcinoma cells

Figure 13-5B. Squamous Cell Carcinoma. H&E,

108

Squamous cell carcinoma (SCC) is the second most common form of skin neoplasm. It originates from keratinocytes of the epidermis. This carcinoma is characterized by a slow-growing reddish or ulcerated lesion with hard, raised borders. It is often found in sun-exposed areas, with a high incidence in elderly male Caucasians. Prolonged sun exposure, chronic inflammatory lesions, and genetic factors, especially p53 tumor suppressor gene mutations, contribute to the development of the disease. SCCs called actinic keratoses commonly arise in premalignant lesions on sun-damaged skin. Carcinoma cells have enlarged and hyperchromatic nuclei with variable differentiation, some lesions producing abundant keratin. Treatment includes surgical excision, cryosurgery, electrosurgery, radiation therapy, and topical treatment.

CLINICAL CORRELATION

B

Lobe of basal cell carcinoma with squamous diffentiation

Peripheral palisading

Figure 13-6B. Basal Cell Carcinoma. H&E, 50

Basal cell carcinoma is the most common form of malignant skin neoplasm. It originates from the basal layer of epidermis and often occurs on sun-exposed areas. Basal cell carcinoma rarely metastasizes and is usually non–life-threatening if addressed early. Local invasion may damage surrounding tissues causing cosmetic concerns. Genetics and long-term exposure to ultraviolet light and arsenical compounds contribute to the disease. Clinically, basal cell carcinoma appears as pearly white nodules or waxy bumps on the face or neck with telangiectatic blood vessels. Subtypes of basal cell carcinoma include nodular, superficial, pigmented, and

fibrosing. Histologic features include a lobular growth pattern of malignant basal cells with peripheral palisading and retraction of lobules from the surrounding stroma. Treatment includes surgical excision, cryosurgery, curettage, and electrodessication.

Langerhans

cells

Melanocytes

H&E, 281

Keratinocytes make up the bulk of the epidermis, but there are additional cell types: melanocytes, Merkel cells, and Langerhans cells. All three types of cells have clear cytoplasm and are sometimes called clear cells. It is difficult to distinguish among them in H&E-stained sections. Melanocytes and Merkel cells are both located in the stratum basale where they are scattered among the basal cuboidal cells. In contrast, Langerhans cells are typically found in the stratum spinosum. The functions of the three cells are quite different: (1) Melanocytes produce melanin granules and insert them into keratinocytes. (2) Merkel cells are receptor cells, that establish synaptic contacts with sensory nerve terminals; they have cytoplasmic granules, which contain neurotransmitters (Fig. 13-2). (3) Langerhans cells are monocyte derivatives, which play an important role in capturing antigens and presenting them to lymphocytes, thereby participating in the cutaneous immune response. Langerhans cells make no desmosome junctions with neighbors; indeed, their function requires that they be motile so that they can transport any captured antigens from the epidermis to lymph nodes deep to the skin.

B

Nuclei of keratinocytes

Melanin granules

Melanocyte processes

Nucleus of the melanocyte

Basal lamina of epidermis

Collagen fibrils in the dermis

CLINICAL CORRELATIONS

A

Melanoma (tumor) cells

Figure 13-8A. Malignant Melanoma. H&E, 198.

Melanoma is an aggressive malignant skin neoplasm originating from melanocytes of the skin. It is characterized by significant morphologic diversity, with skin lesions of irregular shapes and various degrees of pigmentation. Melanoma metastasizes via the lymphatic system. Malignant melanoma is less common than basal cell or SCCs, but it causes the majority of deaths from skin cancer. Genetic factors and sun exposure contribute to the development of the disease. The most common forms of melanoma include superficial spreading melanoma and nodular malignant melanoma. Melanoma cells contain large nuclei with irregular contours, often with prominent nucleoli. Treatment includes surgical excision, chemotherapy, radiation therapy, and immunotherapy.

B

Nests of nevus cells

Figure 13-8B. Melanocytic Nevus. H&E, 22

Melanocytic nevi, commonly referred to as “moles,” may be congenital or acquired, and are composed of melanocytes in nests at the dermo-epidermo junction, in the dermis, or both. If the nevus cells are restricted to the dermis, the lesion is referred to as a dermal melanocytic nevus. If the nevus cells are present only at the dermoepidermo junction, the lesion is referred to as a junctional nevus. If the nevus cells are present in both locations, the term compound nevus is used. Moles typically appear as raised tan to brown soft lesions on sun-exposed or sunrestricted skin. Dysplastic nevi, which may transform to malignant melanoma, are typically larger than most nevi, may have irregular borders, and pigmentary variation. Microscopically, dysplastic nevi may show larger junctional nests that fuse to adjacent nests and cytologic atypia. This image shows a dermal melanocytic nevus with no evidence of dysplasia or atypia.

Accessory Structures

Hair follicle

Sebaceous glands

Figure 13-9A. Sebaceous gland, thin skin (scalp). H&E, 35; inset 66

Sebaceous glands are found in thin skin, usually associated with hair follicles. They are most numerous in the skin of the scalp and face. Sebaceous glands are classified as simple branched acinar glands (see Chapter 3, “Epithelium and Glands”). The secretory cells are lipidproducing cells, arranged into several acini, which open into a short duct. Usually, the ducts of sebaceous glands empty their oily secretion, called sebum, into a hair follicle (Fig. 13-1); however, the ducts sometimes open directly onto the surface of the skin. Sebaceous glands release their products by holocrine secretion, that is, by the disintegration of entire cells. Sebum lubricates the skin and coats and protects hair shafts from becoming brittle. The inset shows an acinus of a sebaceous gland and a nearby arrector pili muscle. Arrector pili muscles are bundles of sympathetically innervated smooth muscle cells that span between hair follicles and the papillary layer of the dermis. They contract to stand the hair up in response to cold or fear (Fig. 13-1).

B

Duct of eccrine sweat gland

Eccrine sweat glands

Figure 13-9B. Eccrine sweat gland, thin skin (scalp). H&E, 248

Eccrine (merocrine) sweat glands can be found in both thin and thick skin over most of the body. They are more numerous in the palms and soles. Eccrine sweat glands produce a clear watery product called sweat. These glands are simple glands in which the secretory cells are arranged into coiled tubules. These glands have long unbranched, but coiled, ducts, which are lined by two layers of cuboidal cells and open directly onto the surface of the skin. Sweat consists mainly of water (99%), some ions (K+, Na+, and Cl−), waste, and metabolic products. Releasing sweat onto the surface of the skin helps adjust body temperature as well as aiding in the excretion of metabolic wastes. The secretory units of eccrine sweat glands contain three cell types.

(1) Dark cells are pyramid-shaped cells containing dark secretory granules. These cells lie toward the lumen of the tubule. (2) Clear cells are also pyramid shaped and have no secretory granules, but have ultrastructural features of ion pumping cells. They are located toward the basement membrane. (3) Myoepithelial cells are not secretory cells. They are spindle-shaped contractile cells, which help to push secretory products into and along the lumen.

C

Lumen of the apocrine sweat gland

Secretory cells (cuboidal cells)

Secretion inside lumen

Figure 13-9C. Apocrine sweat gland, labia. H&E, 248

Apocrine sweat glands are simple coiled tubular glands like the eccrine sweat glands, but their lumens are larger (about 10 times larger than those of the eccrine sweat glands) and their ducts empty into the superficial regions of the hair follicles. The secretory cells of the apocrine glands release their products by shedding part of their apical cytoplasm; this is called apocrine secretion. The tubules of the glands are lined by cuboidal or columnar epithelial cells, depending on the secretory stage. These glands are influenced by hormones and start to function at puberty. They are also called sexual scent glands. They are restricted in location to some specific regions of thin skin, such as the axilla, the areola (nipple), and the perianal and genital areas. Their product is a viscous, thick, milky fluid that contains protein, ammonia, lipids, and carbohydrates. These secretory fluids are odorless when they are released but may have an axillary body odor after degradation by bacteria.

A

outerOuterrootrootsheathsheath

Hair cuticle

Hair medulla

Hair cortex

D. Cui /T. Yang

Connective tissue sheath

Outer root sheath

Inner root sheath

Hair medulla

Hair cuticle

Hair cortex

B

Figure 13-10B. Hair follicles, thin skin (scalp). H&E, 78; inset

172

Hair follicles are the structures that produce the hair and maintain hair growth. They are cellular structures extending from the epidermis into the dermis or hypodermis. The basal region of the hair follicle forms a balloon-shaped structure called the hair bulb, which is composed of the hair root and the dermal papilla. The hair root contains melanocytes and a group of epithelial cells called the matrix or germinal matrix. These cells are capable of cell division and give rise to the inner root sheath and to the hair. The epithelial cells form a cap around the dermal papilla (hair papilla). The dermal papilla contains capillaries and nerve fibers that supply the hair follicle. The interaction between the hair bulb and dermal papilla induces hair follicle differentiation and the growth of the hair. The photomicrograph shows a longitudinal section of hair follicles. The inset shows melanin granules, which give color to the hair. The melanin granules are produced by melanocytes in the hair bulb.

CLINICAL CORRELATION

C

Figure 13-10C. Androgenetic Alopecia. H&E, 50.

Miniaturized Androgenetic alopecia is the most common form of hair follicle loss, affecting 30% to 40% of the adult population.

Males and females have a similar incidence in developing this type of hair loss, characterized by varying degrees of partial hair thinning from the vertex and frontal areas of the scalp. In females, it rarely leads to total baldness. In males, the cause is both genetic and androgen dependent. Patients usually have higher levels of 5-alpha-reductase and androgen receptors. 5-alpha-reductase increases production of dihydrotestosterone, which binds to the androgen receptors in susceptible follicles to trigger the genes to miniaturize the follicles and weaken hair growth. Treatment options include the oral medication finasteride and topical solutions of minoxidil. This cross section of scalp tissue shows variation in hair follicle size with miniaturized follicles and the absence of inflammation.

Figure 13-11A. Nail, finger. H&E, 17

The nail is a translucent, hard, keratinized sheet resting on the tip of each digit. It includes many components: (1) the nail plate, the nail itself, which is hard keratin; (2) the nail root, also called the nail matrix, seen as the lunula in the living state; (3) the nail bed, a layer of epidermis beneath the nail plate; (4) the eponychium, also called the nail cuticle, which is the junction zone between the skin of the finger and the nail plate and which forms a protective seal; (5) the perionychium (nail wall), the skin that surrounds the edge of the nail; and

(6) the hyponychium, the junction seal between the nail plate and the skin of the fingertip. All of the sealed areas at the edges of the nail plate protect the delicate nail matrix and nail bed from dehydration and infection.

B

Eponychium

Nail plate

Nail bed

C

Molluscum bodies

Figure 13-11C. Molluscum Contagiosum. H&E, 53

Molluscum contagiosum is a viral skin infection, caused by the molluscum contagiosum virus, a member of the poxvirus family. The disease is characterized by fleshcolored, dome-shaped, pearly papules with a dimpled center. Lesions are typically 1 to 5 mm in diameter and common on the trunk, arms, and legs. The disease is common in childhood, and usually self-limited in immunocompetent patients. In adults, the disease usually indicates cellular immunodeficiency. The papules are usually nonpainful, but may itch or be complicated by secondary infection. The diagnosis is mainly based on the clinical appearance of the lesions. This slide shows lobules of keratinocytes with large eosinophilic intracytoplasmic inclusions called molluscum bodies within the stratum granulosum and stratum corneum. The treatment may include laser therapies, cryotherapy, or curettage, or there may be no treatment at all.

Periderm

Mesenchymal tissue

Basal layer

Basement membrane

Nucleated erythrocytes

Figure 13-12A. Fetal skin (5–9 weeks). H&E, 331

The two layers (epidermis and dermis) of the skin develop from two different embryonic tissues. The epidermis develops from the ectoderm, and the dermis from the mesoderm. About 4 weeks after conception, the human embryo is covered by a single layer of ectodermal cells, which are loosely arranged on the basement membrane and over the mesenchymal tissue. After 5 weeks, the epidermis has two layers of cells: the superficial layer (periderm) and basal layers. At 2 to 3 months, basal cells are dividing rapidly, and the epidermis becomes several cell layers thick. At the same time, the mesenchyme differentiates into a more mature connective tissue with blood vessels. By 4 months, neural crest cells migrate into the basal layer of the epidermis and differentiate into melanocytes and Merkel cells. The connective tissue layer beneath the epithelium develops into the dermis and a deeper layer, the hypodermis. At about 5 months, the appendages of the skin (hair follicles and glands) start to form. This section shows an early stage of skin development in an embryo. There are only two layers of epithelial cells in the epidermis, and fetal blood vessels are located within the mesenchyme tissue. Nucleated erythrocytes are shown inside the blood vessels.

Epidermis

Basal cells

Accumulated basal cells

(epidermal bud)

Fibroblasts

Dermis

Erythrocytes in

Figure 13-12B. Fetal skin (fifth month). H&E, 438

This section shows a later stage of fetal skin development. The epidermis has formed multiple cell layers, and four layers of epidermis can be distinguished to some extent. The basal cells in the stratum basale layer are highly active and appear as columnshaped cells. The underlying mesenchymal tissue has differentiated into connective tissue (dermis). There are many active fibroblasts in the dermis. An accumulation of basal cells forms a fold called an epidermal bud, which projects into the dermis. These accumulated cells will interact with the dermis and differentiate into appendages (hair follicles and glands).