THE SKIN (INTEGUMENTARY SYSTEM)

Rhonda Ghorbani, MD
Reading: Gartner and Hiatt, pp 229-244; Gartner, Hiatt, Strum, pp 215-227 Learning Objectives: List the basic functions of the skin and describe its overall structure Describe basic skin embryology State the names of the layers of the epidermis and how to distinguish them histologically Explain ultrastructural (electron microscopic) features of the epidermis and the epidermal/dermal junction Describe the process of keratinization in the epidermis, hair, and nail Describe the formation of the water barrier in the epidermis Name the non-keratinocytic cells in the epidermis and state their functions Explain the structure and components of the dermis, including types of nerves and vascular system State the segments and layers of the hair follicle Describe the relationship between hair size and phase of hair growth Describe the structure, location, and function of different types of cutaneous glands Describe the structure and growth of the nail Key Words: arrector pili muscle, dermal papillae (dermal ridges), dermal sheath, dermis, duct of sweat gland, epidermis, external root sheath, glassy membrane, hair bulb, hair follicle, hair matrix, hair papilla, hair root, hair shaft, hypodermis, internal root sheath, interpapillary pegs (rete pegs), Meissner's corpuscle, melanocytes of epidermis, melanosomes (melanin granules), myoepithelial cell, Pacinian corpuscle, papillary layer of dermis, reticular layer of dermis, sebaceous gland, stratum basale, stratum corneum, stratum granulosum, stratum lucidum, stratum spinosum, sweat gland

INTRODUCTION Skin is one of the largest organs in the human body, representing 15-20% of total body weight. It serves many functions, including: S SENSATION (it is a receptor for pain, pressure, touch, temperature) C CONVERSION (of precursor molecules into vitamin D) R REGULATION (of heat) A ABSORPTION (of certain lipid-soluble therapeutic substances) P PROTECTION (against injury of many kinds) & PREVENTION (of water loss) E EXCRETION (of waste products via sweat glands)

The skin can be divided into compartments

EMBRYOLOGY Epidermis: single-layered ectoderm multilayered periderm stratified squamous epithelium o Vernix caseosa: desquamated periderm/epidermis; slippery; protective and aids in birth Dermis: mesoderm mesenchyme dermis composed of multiple cell types Hair: epidermal invagination lanugo hairs (fine, lightly pigmented) mature hairs Melanocytes: neural crest become melanoblasts in mesenchyme mature in epidermis

EPIDERMIS Avascular layers of keratinocytic and non-keratinocytic cells Thickness ranges from 0.1 1.0 mm, depending on location o The terms thin and thick skin refer to the thickness of the epidermis o Thin skin = hairy skin (most of the body) o Thick skin = hairless skin (glabrous skin on palmar/plantar surfaces, i.e. palms/soles)

epidermis

KERATINOCYTES Squamous cells (forming a stratified epithelium) are the major cellular components of the epidermis Migrate from the basal layer to the superficial surface over a period of about 3-4 weeks (approximately 26 days)

Stratum corneum = cornified layer or horny layer Stratum lucidum Stratum granulosum = granular layer Stratum spinosum = spinous layer or prickle cell layer Stratum basale or stratum germinativum = basal layer or germinative layer

UPPER LAYERS OF EPIDERMIS Stratum corneum: Multiple layers of flake-like cells (a.k.a. squames) filled with keratin, without nuclei or organelles Very thick on palms/soles because exposed to friction Eventually shed from skin surface

Stratum lucidum: Homogeneous zone (eosinophilic or red) between strata corneum and granulosum Only present in thick skin Cells contain eleidin (remains of broken-down keratohyaline granules)

Stratum granulosum: 1-3 layers of flattened cells Contains keratohyaline granules (basophilic or dark purple)

LOWER LAYERS OF EPIDERMIS (stratum Malpighi or Malpighian layer)

Stratum spinosum: Often the thickest layer Suprabasal cells are rounder and superficial cells are flatter

Stratum basale: Single row of mitotically-active columnar to cuboidal cells which give rise to other keratinocytes

DESMOSOMES Cells of the stratum spinosum are joined together by desmosomes (a.k.a. macula adherens), which are visible only by electron microscopy Desmosomes are composed of: o Desmogleins and cadherins (transmembrane glycoproteins) o Plaques (composed of desmoplakins): 2 per desmosome (one associated with each cell) Tonofibrils within the cytoplasm of the cell attach to the plaque
desmogleins & cadherins

plaque intermediate filaments

KERATINIZATION Keratohyaline granules are rich in histidine, cystine, and filaggrin Filaggrin combines with cytoplasmic filaments in the process of keratinization Cells undergo keratinization after leaving the stratum granulosum and entering the stratum corneum Keratinization involves breakdown of nucleus and organelles and thickening of plasma membrane Stratum corneum = dead cells with thick plasma membranes, cytoplasmic filaments, and interfilamentous matrix Types of keratin: o Soft keratin: produced via granules (e.g. in the epidermis) o Hard keratin: produced without granules (e.g. in the hair and nails) It is hard because there are many disulfide bonds

WATER BARRIER Lipid-containing lamellar granules (a.k.a. Odland bodies) are produced by the Golgi of keratinocytes and are discharged into the intercellular space by cells of the stratum granulosum Released lipid localizes to the lower stratum corneum, forming a barrier to water loss

NON-KERATINOCYTIC CELLS OF EPIDERMIS There are three types of cells other than keratinocytes within the epidermis: o Melanocytes o Langerhans cells o Merkel cells Of the three cell types, only melanocytes can be seen by routine H&E staining

melanocyte

MELANOCYTES Round cells with clear cytoplasm and basophilic nuclei by H&E stain Have long dendritic processes (not visible by H&E) which extend between keratinocytes Located within the basal layer of the epidermis and in hair follicles Do not establish desmosomal attachments with keratinocytes; instead, they bind to the basal lamina via hemidesmosomes Contain premelanosomes (visible only by electron microscopy), which are membrane-bound spherical and elliptical organelles produced by Golgi Premelanosomes have a finely ordered lamellar internal structure which becomes obscured as melanin is produced and deposited Fully-formed melanosomes are transferred to keratinocytes via melanocytes dendritic processes via cytocrine secretion

The enzyme tyrosinase is responsible for the production of melanin within premelanosomes: tyrosine 3,4-dihydroxyphenylalanine (DOPA) dopaquinone melanin Skin color is influenced by: o Melanin: pigment within melanosomes Types: eumelanin (usual type) and pheomelanin (blonde and red hair) Number of melanocytes in normal skin is constant among races approximately 1 melanocyte per 4-10 basal keratinocytes but may vary from region to region within an individual Degree of skin pigmentation is dependent on melanosomes in keratinocytes their number, size, location within the cell (closer to the nucleus in fair-skinned), stability, and degree of melanization Tanning is due to increased rates of melanin darkening, transfer of melanosomes to keratinocytes, and melanin production Increased pigment shields nucleic acids and proteins from UV radiation Gray hairs are due to decreased number and activity of melanocytes in follicular bulbs o Oxyhemoglobin: in dermal vascular bed o Carotenes: food pigment in fat-containing tissues o Exogenous minerals (e.g. tattoos) o Hemoglobin breakdown products (e.g. hemosiderin, bilirubin)

MERKEL CELLS Located within stratum basale Highest concentration in digits, orogenital regions, and hair follicles Contain electron-dense granules by electron microscopy Establish desmosomal attachments with neighboring cells The base of each cell is in contact with an afferent nerve ending coming up from the dermis Have a receptor function

Langerhans cell Merkel cell

keratinocyte

melanocyte

EPIDERMAL-DERMAL JUNCTION (EDJ) The EDJ forms an undulating interface visible by routine light microscopy as downward projections of the epidermis (epidermal ridges or rete ridges or epidermal pegs or interpapillary pegs) and corresponding upward projections of the papillary dermis (dermal ridges or dermal papillae) o These projections interdigitate to increase surface area and to reinforce the connection (i.e. promote adhesion) between epidermis and dermis o Fingerprints (only present in thick skin) are caused by prominent dermal ridges but are not recognizable as distinct entities by light microscopy

The basal laminae separate the epidermis from the dermis and form a network of components keeping the epidermis connected to the dermis Most EDJ components are only visible by electron microscopy Regions of the EDJ: o Basal keratinocyte o Lamina lucida: electron-lucent zone o Lamina densa: electron-dense zone o Sublamina densa: uppermost papillary dermis Individual structures of the EDJ: o Hemidesmosome: attaches basal keratinocyte to basal lamina Structurally identical to the desmosome except there is no adjacent cell with a complimentary device Has an intracellular component along the basal plasma membrane to which tonofilaments attach Has an extracellular component within the lamina lucida

o o

Anchoring filament: attaches hemidesmosome to basal lamina Extends from inner plasma membrane to lamina densa Anchoring fibril: tethers epidermis to dermis Extends from lamina densa into papillary dermis, terminating on an anchoring plaque Traps collagen within a fibrillar network which enhances attachment

DERMIS Composed of collagen, elastic fibers, ground substance (amorphous extracellular material) and fibroblasts o Collagen accounts for > 70% of skins dry weight o Type I collagen is the most abundant, followed by type III (in adults) o Provides support and strength to the skin Contains blood and lymphatic vessels, nerve endings, and cutaneous adnexal structures Contains striated muscle fibers in the face and neck Contains smooth muscle fibers in the external genitalia and areola Divided into two regions: o Papillary dermis: superficial loose connective tissue o Reticular dermis: deeper dense connective tissue Thicker than papillary dermis, although thickness varies among different parts of the body May contain adipocytes (fat cells)

BLOOD VESSELS Horizontal plexuses of superficial (in upper reticular dermis) and deep (in lower reticular dermis) arterioles and venules joined by vertical communicating vessels Superficial vescular plexus sends capillaries into dermal papillae which nourish the epidermis Blushing results from capillary dilatation

NERVES Efferent nerve fibers: innervate blood vessels, adnexal structures, smooth muscle Free afferent nerve endings: nociceptors (pain receptors) in epidermis and dermis Encapsulated nerve endings: nerve end organs o Meissner corpuscle: mechanoreceptor (tactile) Located high in dermal papillae of palms, soles, digits, nipples, lips Cylindrical or pear-shaped Zigzag arrangement of unmyelinated terminal afferent nerve fibers with supporting (laminar) cells thought to be Schwann cells Can be seen by routine light microscopy but difficult to locate o Pacinian corpuscle: mechanoreceptor (pressure) Located in deep dermis or subcutis of weight-bearing and sensitive areas Ovoid; resembles a cut onion Contains a terminal afferent nerve fiber which loses its myelin after entering the corpuscle, and has supporting (laminar) cells thought to be Schwann cells

Meissner corpuscle
Plate 11-4, Figure 3, pg 233

Pacinian corpuscle
Plate 11-4, Figure 4, pg 233

CUTANEOUS ADNEXAL STRUCTURES (SKIN ADNEXAE) There are different types of adnexal structures within the skin, mainly within the dermis: o Pilosebaceous unit = hair follicle + sebaceous gland Sebaceous glands may exist independently in limited locations o Eccrine gland o Apocrine gland

HAIR FOLLICLE Present over entire body except: sides and volar surfaces of hands/feet, lips, around urogenital orifices Rate of hair growth: few tenths of 1 mm/day Hair functions: protection (of nasal passage from particulate matter, of scalp from sun, of eyes from sun and sweat), reduction of heat loss, decoration

SEGMENTS OF THE HAIR FOLLICLE Infundibulum: from skin surface to opening of sebaceous duct Isthmus: from opening of sebaceous duct to arrector pili muscle insertion

Inferior segment: from arrector pili muscle insertion to base of follicle

Plate 11-2, Figure 1, pg 229

The infundibulum is a continuation of the epidermis o It contains the pilosebaceous canal, through which the hair shaft and sebum pass o The intraepidermal segment is called the acrotrichium The arrector pili muscle is a bundle of smooth muscle which attaches to the connective sheath surrounding the hair follicle o Arrector pili muscle contraction results in goose pimples (erect hair follicles) o The hair bulb is the bulbous base of the follicle which contains the dermal hair papilla (a connective tissue invagination) and the pluripotential hair matrix (which gives rise to the six cell layers of the hair and inner root sheath) Bulb

Dermal hair papilla

Plate 11-3, Figure 1, pg 231

Phases of hair growth o Anagen (growing) o Catagen (involuting) o Telogen (resting)

ANAGEN

CATAGEN

TELOGEN

Hair length is related to the amount of hair in the anagen phase; therefore, the anagen phase lasts for years on the scalp but is shorter for other regions of the body Hair size: o Terminal: long, coarse, heavily pigmented; produced by long follicles; spend a long time in anagen; e.g. scalp, axilla, pubis o Vellus: short, thin, lightly pigmented; produced by small follicles; spend a long time in telogen Conversion of terminal to vellus hairs is one of the causes of baldness Hair follicle layers from outermost to innermost: o Connective tissue (fibrous) sheath o Glassy (basement) membrane o External (outer) root sheath: layer of clear (due to abundant glycogen) cells continuous with the basal layer of the epidermis; does not arise from the hair matrix o Internal (inner) root sheath: dissolves at the level of the sebaceous duct opening Henles layer: first layer to cornify Huxleys layer Cuticle o Hair (a.k.a. hair shaft): keratinized Cuticle Cortex Medulla: last layer to cornify

Graphic 11-2, pg 225

HAIR FOLLICLE IN CROSS-SECTION

Plate 11-3, Figure 2, pg 231

Melanin production by melanocytes in the hair follicle contributes to hair shaft pigmentation Hair follicle keratinization: o Hair shaft layers (medulla, cortex, and cuticle) keratinize without granules; thus, hair keratin is hard keratin o Inner root sheath layers keratinize via trichohyaline granules, which stain eosinophilic (in contrast to basophilic keratohyaline granules in the epidermis); thus, inner root sheath keratin is soft keratin When fully keratinized cells of the inner root sheath reach the isthmus, they disintegrate; therefore, they do not contribute to the exiting hair o Outer root sheath keratinization is called tricholemmal keratinization (tricho- meaning hair), and it also occurs without granules, producing hard keratin This occurs at the isthmus, after the inner root sheath has disintegrated

SEBACEOUS GLAND Present in all skin except palms and soles Most numerous and most productive on scalp and face Largest on nose, forehead, and upper back Hormonally responsive (therefore, well-formed in neonates and during the reproductive years, but small and inactive during other periods of life) Formed by cells of the outer root sheath, usually several lobulated glands (saccules) to one hair follicle Periphery of gland: germinative (basal) cells Center of gland: larger cells filled with lipid vacuoles Central cells disintegrate to form an oily product called sebum (holocrine secretion) Sebum is discharged into the sebaceous duct, which opens into the sebaceous canal in the lower infundibulum of the hair follicle

Graphic 11-2, pg 225

ECCRINE GLAND (SWEAT GLAND) Located over the entire body except: lips, some external genital structures, external auditory canal Embryology: downgrowths from periderm into mesenchyme Highest concentration in the palms, soles, forehead, axilla [note: in these regions, the eccrine glands respond primarily to emotional stimuli, whereas those in other regions respond to thermal stimuli] Functions: thermoregulation (cooling results from sweat evaporation) and excretion Secretory portion: o Located in deep dermis or upper subcutis o 2 different types of secretory cells: staining differences may not be prominent by H&E Clear cells: contain glycogen; located between dark cells and myoepithelial cells Dark cells: contain mucopolysaccharide; located luminally o Merocrine secretion o Surrounded by a row of myoepithelial cells, which contract to move secretions out of gland

Duct portion: o Stratified cuboidal epithelium without myoepithelial cells o Leaves the secretory portion as a coiled duct, then becomes straight o Spirals through the epidermis to the skin surface as the acrosyringium Sweat is a watery solution low in protein; it contains NaCl, urea, uric acid, and ammonia Innervated by the sympathetic nervous system and stimulated by cholinergic transmitters in response to heat and acute stress

APOCRINE GLAND Located in axilla, areola, perineum, circumanal region, external genitalia, external ear canal (ceruminous glands), and eyelid (Molls glands) Small and nonfunctional until puberty Secretory portion: o Located in deep dermis or upper subcutis o Up to 10x greater diameter than eccrine gland o Single row of cuboidal cells with abundant eosinophilic cytoplasm o Called apocrine because it looks like the cell apex is being pinched off (a.k.a. decapitation secretion), but it is actually merocrine (exocytotic) secretion o Surrounded by a row of myoepithelial cells, which contract to move secretions out of gland

Duct portion: o Two layers of cuboidal cells and an inner cuticle but no myoepithelial cells o Travels from the secretory portion and empties into the infundibulum of the hair follicle, above the entrance of the sebaceous duct Considered a type of sweat gland but are not the sweat glands Secreted product becomes odiferous as the result of bacterial decomposition Innervated by sympathetic nervous system and stimulated by adrenergic transmitters in response to emotional and sensory stimuli

SUBCUTIS (HYPODERMIS; PANNICULUS ADIPOSUS; SUBCUTANEOUS FAT) Deep to dermis and superficial to skeletal muscle Lobules of adipose tissue surrounded by fibrous tissue septae

NAIL

Nail plate: keratinized plate on the dorsal surface of the terminal digits o Complete regeneration after removal: 5-6 months on finger & 1-1.5 years on toe o Inserts into lateral and proximal grooves in skin o Overhung by lateral nail fold and proximal nail fold, which are skin folds Nail bed: layers of epithelial cells upon which the nail plate rests o Continuous with strata basale and spinosum of epidermis o Does not have a stratum granulosum o Has long, narrow, sometimes pointed rete ridges and dermal papillae o Overlies a richly vascular dermis that is contiguous with distal phalangeal periosteum

Nail root: proximal part of nail buried under proximal nail fold Nail matrix: germinative epithelium of basaloid cells under the root that differentiates into the nail plate (keratinizes without granules hard keratin) and into some of the cells of the nail bed Lunula: crescent-shaped pale area near the root, just distal to the proximal nail fold o Especially prominent on the thumb o Thought to be due to thick layer of matrix (obscuring pink color imparted by blood vessels) and incomplete cornification of nail Eponychium (cuticle): cornified edge of proximal nail fold o Seals off potential space between fold and nail Hyponychium: epidermal thickening distal to nail bed that joins to undersurface of free edge of nail plate o Separated from volar (palm/sole) skin by the distal groove (not really a groove, but a slightly elevated margin) o Cornifies like volar skin

INTEGUMENT (SKIN) LABORATORY SLIDES 10 and 39 Thick Skin (HEEL or BIG TOE) Begin by holding the slide up to the light 1. The basophilic rim around the outer portion of the tissue on one side is the epidermis. Note that the epidermis is no more than a couple of millimeters thick, even in this example of thick skin. 2. The pink layer underlying the epidermis is the dermis. 3. The subcutaneous tissue (the hypodermis or subcutis) contains adipose tissue, which produces a pale, lacy or lobulated appearance. The dermis itself may contain a small amount of fat, particularly in association with adnexal structures. Now, place your slide under the microscope Questions: What makes thick skin thick What is the commonest cell type in the epidermis? What are the clear cells rounded cells with dense nuclei and pale staining cytoplasm in basal layer)? Name two other cells types in the epidermis PLUS their function(s) Are there blood vessels in the epidermis? 1. Identify the layers of the epidermis (stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, stratum germinativum) and the epidermal-dermal junction. Next, move on to examination of the dermis. Low power: identify papillary and reticular dermis, rete ridges, dermal papillae, superficial and deep blood vessels, eccrine (sweat) glands, and eccrine ducts High power: identify nerve endings; examine the cellular composition of the dermis Meissners corpuscles in dermal papillae may be difficult to see in your slides. These are cylindrical or pear-shaped. View them on the demonstration slide.

Questions: What are some functions of the rete ridges and dermal papillae? What is the major component of the dermis and how does it differ between the papillary and reticular dermis? How can you differentiate between eccrine glands and eccrine ducts based on their location and their cell layers? What skin appendages are not present on this (or any) slide of thick skin?
2. The hypodermis is predominantly composed of adipose tissue. Look for Pacinian corpuscles (although they may not be present on every slide). SLIDE 9 SCALP (thin skin) 1. Identify once more the epidermal and dermal layers. Note the differences between thin skin (H-7) and thick skin (H-135 and H-111): the thinner overall epidermis, reduced thickness of the stratum corneum, absence of an identifiable stratum lucidum, reduced prominence of rete ridges, and presence of pilosebaceous units. 2. Low power: identify the following: Three segments of the hair follicle: infundibulum, isthmus, inferior segment; note how deeply the hair follicles extend in the scalp. Sebaceous gland

3. High power: identify the following: Layers of the hair follicle: inner and outer root sheath Look for red-staining trichohyaline granules in the middle layer of the inner root sheath Other features of the hair follicle Connective tissue sheath: surrounds the follicle Hair bulb: note the keratinocytes and melanocytes Dermal hair papilla: identify the dermal connective tissue extending into the bulb; some slides may show nerve endings and blood vessels in the hair papilla Hair: looks gold-brown and grainy on H&E-stained slides Arrector pili muscle Questions: 3. Why do the cells of the outer root sheath appear clear? 4. Where does the inner root sheath terminate? 5. What type of secretion occurs in the sebaceous gland? SLIDE 51 NIPPLE 1. Examine the epidermis. Note that the basal layer is deeply pigmented, which accounts for the darker skin color of the nipple and areola. 2. Examine the dermis. You may be able to identify a few apocrine glands in the deep reticular dermis. Questions: Does dark skin have more melanocytes and/or more melanosomes? What are the occasional deeply eosinophilic bundles with long, ovoid nuclei in the dermis? SLIDE 52 NAIL Identify the following structures: nail plate, proximal nail fold, nail bed, root, matrix, eponychium, hyponychium. Questions: What type of keratin is produced by the matrix of the nail? How can you tell that by looking at this slide (hint whats NOT there?)? What epidermal layer does the nail plate resemble? What is the common name for the eponychium and what is its function?