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C H A P T E R EPIDERMIS Melanocytes 18 365 368 Skin...

C H A P T E R EPIDERMIS Melanocytes 18 365 368 Skin NAILS 377 SKIN GLANDS 378 Langerhans Cells 370 Sebaceous Glands 378 Merkel Cells 370 Sweat Glands 380 DERMIS 371 SKIN REPAIR 383 SUBCUTANEOUS TISSUE 373 SUMMARY OF KEY POINTS 384 SENSORY RECEPTORS 373 HAIR 374 T he skin is the largest single organ of the body, typically accounting for 15% to 20% of total body weight and, in adults, presenting 1.5 to 2 m2 of surface to the external environment. Also known as the integument (L. integumentum, covering) or cutaneous layer, the skin is composed of mechanoreceptors help regulate the body’s interactions with physical objects. Thermoregulatory: A constant body temperature is normally easily maintained thanks to the skin’s insulating components (eg, the fatty layer and hair on the head) and the epidermis, an epithelial layer of ectodermal origin, its mechanisms for accelerating heat loss (sweat produc- and the dermis, a layer of mesodermal connective tissue tion and a dense superficial microvasculature). (Figure 18–1). At the irregular junction between the dermis Metabolic: Cells of skin synthesize vitamin D3, needed and epidermis, projections called dermal papillae inter- in calcium metabolism and proper bone formation, digitate with invaginating epidermal ridges to strengthen through the local action of UV light on the vitamin’s adhesion of the two layers. Epidermal derivatives include hairs, precursor. Excess electrolytes can be removed in sweat, nails, and sebaceous and sweat glands. Beneath the dermis and the subcutaneous layer stores a significant amount of lies the subcutaneous tissue or hypodermis (Gr. hypo, energy in the form of fat. under + derma, skin), a loose connective tissue layer usually Sexual signaling: Many features of skin, such as containing pads of adipocytes. The subcutaneous tissue binds pigmentation and hair, are visual indicators of health the skin loosely to the underlying tissues and corresponds to involved in attraction between the sexes in all vertebrate the superficial fascia of gross anatomy. species, including humans. The effects of sex phero- The specific functions of the skin fall into several broad mones produced by the apocrine sweat glands and other categories. skin glands are also important for this attraction. Protective: It provides a physical barrier against ther- The dermal-epidermal interdigitations are of the peg- mal and mechanical insults such as friction and against and-socket variety in most skin (Figure 18–1), but they most potential pathogens and other material. Micro- occur as well-formed ridges and grooves in the thick skin organisms that do penetrate skin alert resident lympho- of the palms and soles, which is more subject to friction. cytes and antigen-presenting cells (APCs) in skin and an These ridges and the intervening sulci form distinctive pat- immune response is mounted. The dark pigment melanin terns unique for each individual, appearing as combinations in the epidermis protects cell nuclei from ultraviolet (UV) of loops, arches, and whorls, called dermatoglyphs, also radiation. Skin is also a permeability barrier against known as fingerprints and footprints. Skin is elastic and can excessive loss or uptake of water, which has allowed for expand rapidly to cover swollen areas and, like the gut lin- terrestrial life. Skin’s selective permeability allows some ing, is self-renewing throughout life. In healthy individuals lipophilic drugs such as certain steroid hormones and injured skin is repaired rapidly. The molecular basis of skin medications to be administered via skin patches. healing is increasingly well understood and provides a basis Sensory: Many types of sensory receptors allow skin to for better understanding of repair and regeneration in other constantly monitor the environment, and various skin organs. 364  Epidermis 365 FIGURE 18–1 Layers and appendages of skin. C H A P T E R 1 8 Skin Epidermis Epidermal ridges Dermal papillae Epidermis Papillary layer Dermis Reticular layer Tactile (sensory) receptor Artery Vein Subcutaneous layer Areolar connective tissue Adipose connective tissue Diagrammatic overview of skin, showing the major layers sebaceous glands), the vasculature, and the major sensory and epidermal appendages (hair follicles, sweat, and receptors. ❯ EPIDERMIS epithelia, the stratified squamous epidermis lacks microvas- culature, its cells receiving nutrients and O2 by diffusion from The epidermis consists mainly of a stratified squamous kera- the dermis. tinized epithelium composed of cells called keratinocytes. From the dermis, the epidermis consists of four layers of There are also three much less abundant epidermal cell keratinocytes (or five layers in thick skin, Figure 18–2): types: pigment-producing melanocytes, antigen-presenting Langerhans cells, and tactile epithelial cells called Merkel The basal layer (stratum basale) is a single layer of cells (Figure 18–2). basophilic cuboidal or columnar cells on the basement The epidermis forms the major distinction between thick membrane at the dermal-epidermal junction (Figures skin (Figure 18–2a), found on the palms and soles, and thin 18–2 and 18–3). Hemidesmosomes in the basal cell skin (Figure 18–3) found elsewhere on the body. The desig- membranes join these cells to the basal lamina, and nations “thick” and “thin” refer to the thickness of the epi- desmosomes bind the cells of this layer together in their dermal layer, which alone varies from 75 to 150 μm for thin lateral and upper surfaces. The stratum basale is char- skin and from 400 to 1400 μm (1.4 mm) for thick skin. Total acterized by intense mitotic activity and contains, along skin thickness (epidermis plus dermis) also varies according with the deepest part of the next layer, progenitor cells to the site. For example, full skin on the back is about 4 mm for all the epidermal layers. In addition to the basal stem thick, whereas that of the scalp is about 1.5 mm thick. Like all cells for keratinocytes found here, a niche for such cells 366 CHAPTER 18 Skin FIGURE 18–2 Layers (strata) of epidermis in thick skin. Dead keratinocytes Stratum corneum Stratum lucidum Stratum granulosum Living keratinocyte Stratum spinosum Stratum basale Melanocyte Epidermal dendritic cell Basement membrane Dermis Tactile cell Sensory nerve ending a b (a) Micrograph shows the sequence of the epidermal layers coiling to a surface pore through all the strata. X100. H&E. in thick skin and the approximate sizes and shape of kerati- (b) Diagram illustrating the sequence of the epidermal layers nocytes in these layers. Also shown are the coarse bundles also indicates the normal locations of three important nonke- of collagen in the dermis and on the far left, the duct from a ratinocyte cells in the epidermis: melanocytes, a Langerhans sweat gland entering the epidermis from a dermal papilla and cell, and a tactile Merkel cell. also occurs in the hair follicle sheaths that are continu- some cells may still divide and this combined zone is ous with the epidermis. The human epidermis is renewed sometimes called the stratum germinativum. The kera- about every 15 to 30 days, depending on age, the region tin filaments assemble here into microscopically visible of the body, and other factors. An important feature of bundles called tonofibrils that converge and terminate all keratinocytes in the stratum basale is the cytoskel- at the numerous desmosomes holding the cell layers to- etal keratins, intermediate filaments about 10 nm in gether. The cells extend slightly around the tonofibrils on diameter. During differentiation, the cells move upward both sides of each desmosome (and the extensions elon- and the amount and types of keratin filaments increase gate if the cells shrink slightly during histologic process- until they represent half the total protein in the superficial ing), leading to the appearance of many short “spines” or keratinocytes. prickles at the cell surfaces (Figure 18–4). The epidermis of thick skin subject to continuous friction and pressure ❯❯ MEDICAL APPLICATION (such as the foot soles) has a thicker stratum spinosum with more abundant tonofibrils and desmosomes. Friction blisters are lymph-filled spaces created between the epidermis and dermis of thick skin by excessive rub- bing, as with ill-fitting shoes or hard use of the hands. If ❯❯ MEDICAL APPLICATION continued, such activity produces protective thickening In adults, one-third of all cancers originate in the skin. and hardening of the outer cornified epidermal layers, Most of these derive from cells of the basal or spinous seen as corns and calluses. layers, producing, respectively, basal cell carcinomas and squamous cell carcinomas. Fortunately, both types of % The spinous layer (stratum spinosum) is normally the tumors can be diagnosed and excised early and conse- thickest layer, especially in the epidermal ridges (Figures quently are rarely lethal. Skin cancer shows an increased 18–2 and 18–3), and consists of generally polyhedral cells incidence in fair-skinned individuals residing in regions having central nuclei with nucleoli and cytoplasm with high amounts of solar radiation. actively synthesizing keratins. Just above the basal layer,  Epidermis 367 FIGURE 18–3 Layers of epidermis in thin skin. The granular layer (stratum granulosum) consists of three to five layers of flattened cells, now undergoing C H A P T E R the terminal di%erentiation process of keratinization. Their cytoplasm is filled with intensely basophilic masses (Figures 18–2 and 18–3; Figure 18–5) called keratohya- C line granules. These are dense, non–membrane-bound G masses of filaggrin and other proteins associated with S the keratins of tonofibrils, linking them further into large 1 8 cytoplasmic structures. Characteristic ultrastructural fea- S tures in cells of the granular layer are the membranous, Skin Epidermis Golgi-derived lamellar granules, small ovoid (100 by EP DP 300 nm) structures with many lamellae containing vari- ous lipids. Among the last activities of the keratinocytes, B the lamellar granules undergo exocytosis, producing a lipid-rich, impermeable layer around the cells. This D material forms a major part of the skin’s barrier against water loss. Formation of this barrier, which appeared first in ancestral reptiles, was a key evolutionary process The interface between dermis and epidermis in thin skin is that permitted animals to develop on land. Together, held together firmly by interlocking epidermal ridges or pegs keratinization and production of the lipid-rich layer also (EP) and dermal papillae (DP). The dermis (D) of thin skin is more cellular and well vascularized than that of thick have a crucial sealing e%ect in skin, forming the barrier skin, with elastin and less coarse bundles of collagen. The to penetration by most foreign materials. epidermis usually shows only four layers in thin skin: the The stratum lucidum, found only in thick skin, consists one-cell thick stratum basale (B) containing most mitotic of a thin, translucent layer of flattened eosinophilic kera- cells; the stratum spinosum (S) where synthesis of much tinocytes held together by desmosomes (Figures 18–1 keratin and other proteins takes place; the stratum granu- losum (G); and the stratum corneum (C), consisting of dead and 18–5). Nuclei and organelles have been lost, and the squames composed mostly of keratin. X240. H&E. cytoplasm consists almost exclusively of packed keratin filaments embedded in an electron-dense matrix. The stratum corneum (Figures 18–2 and 18–3) consists of 15 to 20 layers of squamous, keratinized cells filled with birefringent filamentous keratins. Keratin filaments contain at least six di%erent polypeptides with molecular FIGURE 18–4 Keratinocytes of the stratum spinosum. a b c (a) A section of epidermal stratum spinosum of thick skin, (c) Detail of the desmosomes joining two cells showing inter- showing cells with numerous short cytoplasmic projections mediate filaments associated with desmosomes. X40,000. (arrow). X400. PT. (b) TEM of a single spinous keratinocyte with surface projec- tions (arrows). X8400. 368 CHAPTER 18 Skin Important features of the epidermal strata are summa- FIGURE 18–5 Stratum granulosum and stratum rized in Table 18–1. lucidum: thick skin. ❯❯ MEDICAL APPLICATION In the chronic skin condition called psoriasis, keratocytes are typically produced and differentiate at accelerated C rates, causing at least slight thickening of the epidermal layers and increased keratinization and desquamation. Psoriasis is caused by overactive T lymphocytes that trigger an autoimmune reaction in the skin, which can also lead to inflammation with redness, irritation, itching, and scaling, with a defective skin barrier. L G Melanocytes The color of the skin is the result of several factors, the most important of which are the keratinocytes’ content of melanin and carotene and the number of blood vessels in the dermis. Eumelanins are brown or black pigments produced by S the melanocyte (Figures 18–6 and 18–7), a specialized cell of the epidermis found among the cells of the basal layer and in hair follicles. The similar pigment found in red hair is called pheomelanin (Gr. phaios, dusky + melas, black). Melano- In keratinocytes moving upward from the stratum spinosum cytes are neural crest derivatives that migrate into the embry- (S), differentiation proceeds with the cells becoming filled onic epidermis’ stratum basale, where eventually one mela- with numerous large, amorphous masses of protein called nocyte accumulates for every five or six basal keratinocytes keratohyaline granules. (600-1200/mm2 of skin). They have pale-staining, rounded Cells with these basophilic granules make up the stratum granulosum (G), where keratin filaments are cross-linked with cell bodies attached by hemidesmosomes to the basal lamina, filaggrin and other proteins from these granules to produce but lacking attachments to the neighboring keratinocytes. tight bundles filling the cytoplasm and flattening the cells. Several long irregular cytoplasmic extensions from each mela- Smaller organelles called lamellar granules undergo exocy- nocyte cell body penetrate the epidermis, running between tosis in this layer, secreting a lipid-rich layer around the cells the cells of the basal and spinous layers and terminating which makes the epidermis impermeable to water. Together, the lipid envelope and the keratin-filled cells determine most in invaginations of 5 to 10 keratinocytes. Ultrastructur- of the physical properties of the epidermis. ally a melanocyte has numerous small mitochondria, short The cells leaving the stratum granulosum, still bound cisternae of RER, and a well-developed Golgi apparatus together by desmosomes, undergo terminal differentiation and (Figure 18–6). in thick skin appear as a dense, thin layer called the stratum The first step in melanin synthesis is catalyzed by tyrosi- lucidum (L). Here proteins are dispersed through the tonofibril bundles, giving this layer a regular, “clear” appearance. nase, a transmembrane enzyme in Golgi-derived vesicles In the most superficial stratum corneum (C), the cells have (Figure 18–7a). Tyrosinase activity converts tyrosine into lost nuclei and cytoplasm, consisting only of flattened, 3,4-dihydroxyphenylalanine (DOPA), which is then further keratinized structures called squames bound by hydrophobic, transformed and polymerized into the different forms of mela- lipid-rich intercellular cement. At the surface they are worn nin. Melanin pigment is linked to a matrix of structural pro- away (thick skin) or flake off (thin skin). X560. H&E. teins and accumulates in the vesicles until they form mature elliptical granules about 1 μm long called melanosomes (Figure 18–7b). masses ranging from 40 to 70 kDa, synthesized during Melanosomes are then transported via kinesin to the tips cell differentiation in the immature layers. As they form, of the cytoplasmic extensions. The neighboring keratinocytes keratin tonofibrils become heavily massed with filaggrin phagocytose the tips of these dendrites, take in the melano- and other proteins in keratohyaline granules. By the somes, and transport them by dynein toward their nuclei. The end of keratinization, the cells contain only amorphous, melanosomes accumulate within keratinocytes as a supra- fibrillar proteins with plasma membranes surrounded nuclear cap that prior to keratinization absorbs and scatters by the lipid-rich layer. These fully keratinized or corni- sunlight, protecting DNA of the living cells from the ionizing, fied cells called squames are continuously shed at the mutagenic effects of UV radiation. epidermal surface as the desmosomes and lipid-rich cell Although melanocytes produce melanosomes, the kera- envelopes break down. tinocytes are the melanin depot and contain more of this pig-  Epidermis 369 TABLE 18–1 Skin layers and the subcutaneous layer. C H A P T E R Layer Specific Layer Description Epidermis Stratum corneum Most superficial layer; 20-30 layers of dead, flattened, anucleate, keratin-filled keratinocytes; protects against friction and water loss Stratum corneum Stratum lucidum 2-3 layers of anucleate, dead cells; seen only in thick skin 1 8 Stratum lucidum Stratum granulosum 3-5 layers of keratinocytes with distinct kerato- Stratum granulosum hyaline granules Skin Epidermis Stratum spinosum Several layers of keratinocytes all joined by Stratum spinosum desmosomes; Langerhans cells present Stratum basale Stratum basale Deepest, single layer of cuboidal to low columnar cells in contact with basement membrane; mitosis occurs here; melanocytes and Merkel cells also Dermis Papillary layer More superficial layer of dermis; composed of areolar connective tissue; forms dermal papillae; contains subpapillary vascular plexus Reticular layer Deeper layer of dermis; dense irregular Papillary layer connective tissue surrounding hair follicles, sebaceous glands and sweat glands, nerves, and deep plexus of blood vessels extending into subcutaneous layer Reticular layer Subcutaneous layer No specific layers Not considered part of the integument; deep to dermis; composed of areolar and adipose connective tissue ment than the cells that make it. One melanocyte plus the are not clear, but they may include environmental, genetic, keratinocytes into which it transfers melanosomes make up an or autoimmune conditions. epidermal-melanin unit. The density of such units in skin is similar in all individuals. Melanocytes of people with ancestral origins near the equator, where the need for protection against In regions with much less sunlight such as northern the sun is greatest, produce melanin granules more rapidly Europe, the small amount of UV radiation penetrating dark and accumulate them more abundantly in keratinocytes. skin barely sustains adequate vitamin D3 synthesis. Individuals with ancestry there have one or more genetic polymorphisms that affect steps in melanin formation and cause more lightly ❯❯ MEDICAL APPLICATION pigmented keratinocytes that have increased UV penetration Albinism is a congenital disorder producing skin hypopig- and vitamin D3 synthesis. mentation due to a defect in tyrosinase or some other Darkening of the skin, or tanning, after exposure to solar component of the melanin-producing pathway. An acquired radiation at wavelengths of 290 to 320 nm is a two-step pro- condition called vitiligo involves skin depigmentation, often cess. A physicochemical reaction darkens preexisting melanin. only in affected patches, due to the loss or decreased At the same time, paracrine factors secreted by keratinocytes activity of melanocytes. The causes of melanocyte loss experiencing increased UV radiation accelerate melanin syn- thesis and its accumulation in the epidermis. 370 CHAPTER 18 Skin FIGURE 18–6 Melanocytes. K M CE a M Vesicle filled with melanin Melanin pigment in keratinocyte MG MG Melanin pigment Melanocyte G Basement membrane c BL b (a) Micrograph shows melanocytes (M) in the epidermal (c) Ultrastructurally, a melanocyte is located on the basal basal layer which synthesize melanin granules and transfer lamina (BL) and has well-developed Golgi complexes (G) producing them into neighboring keratinocytes of the basal and spinous the vesicles in which melanin is synthesized. As they fill, these layers. Typically melanocytes are pale-staining cells on the vesicles become melanin granules (MG), which accumulate at basement membrane, with lower total melanin content than the tips of the dendritic cytoplasmic extensions (CE) before the keratinocytes. X400. H&E. transfer to keratinocytes (K). X14,000. (b) Diagram of a melanocyte shows the irregular cytoplasmic processes between neighboring keratinocytes for transfer of melanin to those cells. ❯❯ MEDICAL APPLICATION as immune dendritic cells in other organs (see Chapter 14). Microorganisms cannot penetrate the epidermis without alert- Melanocytes can normally proliferate in skin to produce ing these dendritic cells and triggering an immune response. moles, or benign melanocytic nevi of various types. Langerhans cells, along with more scattered epidermal lym- Changes in the size or appearance of moles are some- phocytes and other APCs in the dermis, make up a major times indicative of dysplasia that can progress further to component of the skin’s adaptive immunity. malignant melanoma. Dividing rapidly, malignantly trans- Because of its location, the skin is continuously in close formed melanocytes often penetrate the basal lamina, contact with many antigenic molecules. Various epidermal enter the dermis, and metastasize by invading blood and features participate in both innate and adaptive immunity (see lymphatic vessels. Chapter 14), providing an important immunologic compo- nent to the skin’s overall protective function. Langerhans Cells Merkel Cells Antigen-presenting cells (APCs) called Langerhans cells, Merkel cells, or epithelial tactile cells, are sensitive mecha- which are usually most clearly seen in the spinous layer, noreceptors essential for light touch sensation. Joined by desmo- represent 2% to 8% of the epidermal cells. Cytoplasmic pro- somes to keratinocytes of the basal epidermal layer, Merkel cells cesses extend from these dendritic cells between keratino- resemble the surrounding cells but with few, if any, melanosomes. cytes of all the layers, forming a fairly dense network in the They are abundant in highly sensitive skin like that of fingertips epidermis (Figure 18–8). Langerhans cells bind, process, and at the bases of some hair follicles. Merkel cells originate from and present antigens to T lymphocytes in the same manner the same stem cells as keratinocytes and are characterized by  Dermis 371 FIGURE 18–7 Melanosome formation. C H A P T E R I 1 8 Skin Dermis Melanin granule (no tyrosinase activity) II Melanosome III Golgi (tyrosinase + melanin) Melanosome II (tyrosinase + melanin) III Tyrosinase synthesis IV Rough ER Tyrosine The diagram of a melanocyte shows the main features of the internal matrix completely filled with melanin. The mature melanin formation. The granules containing melanin mature granules are ellipsoid, approximately 0.5 by 1 μm in size, and through four stages that are characterized ultrastructurally, as visible by light microscopy. shown on the right. Tyrosinase is synthesized in the rough ER, Melanin granules are transported to the tips of the processed through the Golgi apparatus, and accumulates in processes of melanocyte and are then transferred to the vesicles that also have a fine granular matrix of other proteins neighboring keratinocytes of the basal and spinous layers. (stage I melanosomes). Melanin synthesis begins in the ovoid In keratinocytes the melanin granules are transported to a stage II melanosomes, in which the matrix has been organized region near the nucleus, where they accumulate as a supra- into parallel filaments on which polymerized melanin is depos- nuclear cap shading the DNA against the harmful effects of ited and accumulates in stage III. A mature melanin granule UV radiation. (stage IV) has lost tyrosinase and other activities and has small, Golgi-derived dense-core neurosecretory granules con- ❯ DERMIS taining peptides (Figure 18–9). The basolateral surfaces of the cells contact expanded terminal discs of unmyelinated sensory The dermis is the layer of connective tissue (Figures 18–1 and fibers penetrating the basal lamina (Figure 18–9). 18–2) that supports the epidermis and binds it to the subcuta- neous tissue (hypodermis). The thickness of the dermis varies ❯❯ MEDICAL APPLICATION with the region of the body and reaches its maximum of 4 mm on the back. The surface of the dermis is very irregular and Merkel cells are of clinical importance because Merkel has many projections (dermal papillae) that interdigitate with cell carcinomas, though uncommon, are very aggressive projections (epidermal pegs or ridges) of the epidermis (see and difficult to treat. Merkel cell carcinoma is 40 times Figure 18–1), especially in skin subject to frequent pressure, less common than malignant melanoma but has twice the where they reinforce the dermal-epidermal junction. mortality of that disease. 372 CHAPTER 18 Skin FIGURE 18–8 Langerhans cells. E F a b Langerhans cells are dendritic APCs of the epidermis where (b) Face-on view of an epidermal sheet stained using the they comprise an important defense against pathogens and same antibody showing the network of Langerhans cells environmental insults. Like other APCs, they develop in the among the other epidermal cells, which detects invading micro- bone marrow, move into the blood circulation, and finally organisms. After sampling the invaders’ antigens, Langerhans migrate into stratified squamous epithelia where they are cells leave the epidermis and travel to the nearest lymph difficult to identify in routinely stained sections. (a) Section of node to elicit lymphocytes that can mount a collective immune immunostained skin shows Langerhans cells (yellow) abun- response. X200. Anti-langerin/CD207. dant in hair follicles (F), where many microorganisms live, and (Reproduced, with permission, from Romani N et al. Acta throughout the epidermis (E). Keratin of the epidermis and Path Micro Immunol Scandinavica. 2003;111:725.) follicles is stained green. X40. Antibodies against langerin/ CD207 and keratin. A basement membrane always occurs between the stra- anchoring fibrils of type VII collagen insert into the basal tum basale and the dermis, and follows the contour of the inter- lamina, helping to bind the dermis to the epidermis. digitations between these layers. As described in Chapter 4, The underlying reticular layer is much thicker, consists this membrane is a composite structure consisting of the of dense irregular connective tissue (mainly bundles of basal lamina and the reticular lamina, and can usually be type I collagen), with more fibers and fewer cells than the seen with the light microscope. Nutrients for keratinocytes papillary layer. A network of elastic fibers is also present diffuse into the avascular epidermis from the dermal vascula- (Figure 18–10), providing elasticity to the skin. Between ture through this basement membrane. the collagen and elastic fibers are abundant proteogly- cans rich in dermatan sulfate. ❯❯ MEDICAL APPLICATION Abnormalities of the dermal-epidermal junction can lead ❯❯ MEDICAL APPLICATION to one type of blistering disorder (bullous pemphigoid). With age, collagen fibers thicken and collagen synthesis Another type of blistering disorder (pemphigus) is caused decreases. In old age, extensive cross-linking of col- by autoimmune damage to intercellular junctions between lagen fibers and the loss of elastic fibers, especially keratinocytes. after excessive exposure to the sun (solar elastosis), cause the skin to become more fragile, lose its supple- The dermis contains two sublayers with indistinct bound- ness, and develop wrinkles. The epidermis also normally aries (see Figure 18–1; Table 18–1): thins and becomes more transparent during aging. In several disorders, such as cutis laxa and Ehlers-Danlos The thin papillary layer, which includes the dermal syndromes, there is a considerable increase in skin and papillae, consists of loose connective tissue, with types ligament extensibility caused by defective collagen-fibril I and III collagen fibers, fibroblasts and scattered mast processing. cells, macrophages, and other leukocytes. From this layer,  Sensory Receptors 373 around hair follicles, ending at epithelial and dermal receptors FIGURE 18–9 Merkel or tactile cell. shown in Figure 18–11. Autonomic effector nerves to dermal C H A P T E R sweat glands and smooth muscle %bers in the skin of some areas are postganglionic %bers of sympathetic ganglia; no parasympathetic innervation is present. 1 8 ❯ SUBCUTANEOUS TISSUE The subcutaneous layer (see Figure 18–1) consists of loose Skin Sensory Receptors N connective tissue that binds the skin loosely to the subjacent organs, making it possible for the skin to slide over them. This layer, also called the hypodermis or superficial fascia, con- tains adipocytes that vary in number in different body regions and vary in size according to nutritional state. The extensive vascular supply at the subcutaneous layer promotes rapid uptake of insulin or drugs injected into this tissue. G N ❯ SENSORY RECEPTORS Merkel cells in the basal epidermal layer have high tactile With its large surface and external location, the skin functions as sensitivity and function as mechanoreceptors. This TEM an extensive receiver for various stimuli from the environment. of a Merkel cell shows a mass of dense-core cytoplasmic granules (G) near the basolateral cell membrane, which is Diverse sensory receptors are present in skin, including both in direct contact with the expanded, disc-like ending of a simple nerve endings with no Schwann cell or collagenous sensory nerve (N). X14,000. Inset: Granules are similar in coverings and more complex structures with sensory %bers morphology and content to the granules of many neuroen- enclosed by glia and delicate connective tissue capsules docrine cells. X61,500.) (Figure 18–11). The unencapsulated receptors include the following: The Merkel cells, each associated with expanded nerve Both dermal regions contain a rich network of blood and endings (Figure 18–9), which function as tonic recep- lymphatic vessels. Nutritive vessels form two major plexuses tors for sustained light touch and for sensing an object’s (see Figure 18–1): texture. Free nerve endings in the papillary dermis and Between the papillary and reticular dermal layers lies extending into lower epidermal layers, which respond the microvascular subpapillary plexus, from which primarily to high and low temperatures, pain, and itch- capillary branches extend into the dermal papillae and ing, but also function as tactile receptors. form a rich, nutritive capillary network just below the Root hair plexuses, a web of sensory %bers surround- epidermis. ing the bases of hair follicles in the reticular dermis that A deep plexus with larger blood and lymphatic vessels detects movements of the hairs. lies near the interface of the dermis and the subcutane- ous layer. The encapsulated receptors are all phasic mechanorecep- tors, responding rapidly to stimuli on the skin. Four are rec- In addition to the nutritive function, dermal vascu- ognized in human skin, although only the %rst two are seen in lature has a thermoregulatory function, which involves routine preparations: numerous arteriovenous anastomoses or shunts (see Chapter 11) located between the two major plexuses. The Meissner corpuscles are elliptical structures, 30 to shunts decrease blood flow in the papillary layer to mini- 75 μm by 50 to 150 μm, consisting of sensory axons mize heat loss in cold conditions and increase this flow to winding among flattened Schwann cells arranged facilitate heat loss when it is hot, thus helping maintain a perpendicular to the epidermis in the dermal papillae constant body temperature. Lymphatic vessels begin in the (Figure 18–12a). They initiate impulses when light- dermal papillae and converge to form two plexuses located touch or low-frequency stimuli against skin temporarily with the blood vessels. deform their shape. They are numerous in the %ngertips, The dermis is also richly innervated. Sensory affer- palms, and soles but decline slowly in number during ent nerve %bers form a network in the papillary dermis and aging after puberty. 374 CHAPTER 18 Skin flattened Schwann cells and collagen surrounding a FIGURE 18–10 Elastic fibers of dermis. highly branched, unmyelinated axon (Figure 18–12b). Lamellated corpuscles are specialized for sensing coarse touch, pressure (sustained touch), and vibrations, with distortion of the capsule amplifying a mechanical stimu- lus to the axonal core where an impulse is initiated. Pacinian corpuscles are also found in the connective tissue of organs located deep in the body, including the wall of the rectum and urinary bladder, where they also produce the sensation of pressure when the surrounding tissue is distorted. Krause end bulbs are simpler encapsulated, ovoid structures, with extremely thin, collagenous capsules penetrated by a sensory fiber. They are found primarily in the skin of the penis and clitoris where they sense low- frequency vibrations. Ruffini corpuscles have collagenous, fusiform capsules anchored firmly to the surrounding connective tissue, with sensory axons stimulated by stretch (tension) or twisting (torque) in the skin. ❯ HAIR Hairs are elongated keratinized structures that form within epidermal invaginations, the hair follicles (Figure 18–13). The color, size, shape, and texture of hairs vary according to age, genetic background, and region of the body. All skin has at least minimal hair except the glabrous skin of the palms, soles, lips, glans penis, clitoris, and labia minora. The face has about 600 hairs/cm2 and the remainder of the body has A section of thin skin stained for elastic fibers shows the extensive distribution of these darkly stained fibers among the about 60/cm2. Hairs grow discontinuously, with periods of eosinophilic collagen bundles. In the dermal papillary layer, the growth followed by periods of rest, and this growth does not diameter of fibers decreases as they approach the epider- occur synchronously in all regions of the body or even in the mis and insert into the basement membrane. X100. Weigert same area. elastic stain. The growing hair follicle has a terminal dilation called a hair bulb (Figure 18–13a). A dermal papilla inserts into the base of the hair bulb and contains a capillary network required to sustain the hair follicle. Keratinocytes continuous with those of the basal epidermis cover the dermal papilla. These cells form the matrix of the elongating hair root; the part of a hair ❯❯ MEDICAL APPLICATION extending beyond the skin surface is the hair shaft. The density of tactile Meissner corpuscles in skin can The keratinocytes of the hair bulb are generally similar to be determined approximately by two-point discrimination those in the basal and spinous layers of epidermis. They divide tests. Such neurologic measurements indicate that the rapidly in the region immediately around the dermal papilla number of tactile corpuscles in skin normally declines and then undergo keratinization, melanin accumulation, and during adult life. Loss of tactile corpuscles or reduction terminal di%erentiation. Melanocytes in the hair bulb matrix in their activity can also be detected in scleroderma and transfer melanosomes into the epithelial cells that will later certain other connective tissue disorders that lead to scle- di%erentiate to form the hair. Unlike the epidermis in which rosis (hardening) of the dermis and tightening of the skin. all keratinocytes give rise to the stratum corneum, cells in the hair root matrix di%erentiate with variable amounts and types of keratin. The keratin of hair is harder and more compact Lamellated (pacinian) corpuscles are large oval than that of the stratum corneum, maintaining its structure as structures, approximately 0.5 mm by 1 mm, found deep the hair shaft much longer. in the reticular dermis and hypodermis, with an outer In most thick hairs large, vacuolated, and moderately capsule and 15-50 thin, concentric lamellae of keratinized cells form the central medulla of the hair root  Hair 375 FIGURE 18–11 Tactile receptors. C H A P T E R 1 8 Tactile disc Skin Hair Epidermis Free nerve ending Tactile corpuscle Krause bulb Dermis Ruffini corpuscle Root hair plexus Lamellated corpuscle Subcutaneous layer Skin contains several types of sensory receptors, with or with- More complex, encapsulated tactile receptors are located out capsules of collagen and modified Schwann cells. Most in the dermis and hypodermis, and include Meissner cor- are difficult to see in routine preparations. In the epidermis puscles for light touch, lamellated (pacinian) corpuscles are free nerve endings and tactile discs of nerve fibers associ- detecting pressure and high-frequency vibration, Krause ated with Merkel cells in the basal layer. Both have unencap- end bulbs for low-frequency vibrations/movements, and sulated nerve fibers, as does the root hair plexus around the Ruffini corpuscles detecting tissue distortion. The latter bases of hair follicles in the dermis. They detect light touch or two receptors are less widely distributed in skin and less movement of hair, although epidermal free nerve endings also commonly seen. detect pain and temperature extremes. (Figures 18–13b and 18–14). Heavily keratinized, densely the initial part of the hair root but degenerates above the level packed cells make up the cortex around the medulla. The of the attached sebaceous glands. The external root sheath most peripheral cells of the hair root comprise the cuticle, a covers the internal sheath and extends all the way to the thin layer of heavily keratinized, squamous cells covering the epidermis, where it is continuous with the basal and spinous cortex (Figures 18–13c and 18–14). layers. Separating the hair follicle from the dermis is an acellu- The outermost cells of the hair bulb are continuous lar hyaline layer, the thickened basement membrane called the with the epithelial root sheath, in which two layers can be glassy membrane (Figure 18–14b). The surrounding dermis recognized. The internal root sheath completely surrounds forms a connective tissue sheath. 376 CHAPTER 18 Skin FIGURE 18–12 Meissner and lamellated (pacinian) corpuscles. E TC PC E DP A a b Micrographs show the two most commonly seen sensory recep- length, found among adipose tissue (A) deep in the reticular tors of skin. (a) Meissner tactile corpuscles (TC) are special- dermis or in the subcutaneous tissue. Here the outer connec- ized to detect light touch and are frequently located in dermal tive tissue capsule surrounds 15-50 thin, concentric layers of papillae (DP), partially surrounded by epidermis (E). They are modified Schwann cells, each separated by slightly viscous elliptical, approximately 150 μm long, with an outer capsule interstitial fluid. Several axons enter one end of the corpuscle (from the perineurium) and thin, stacked inner layers of modified and lie in the cylindrical, inner core of the structure. Movement Schwann cells, around which course nerve fibers. X400. H&E. or pressure of this corpuscle from any direction displaces the (b) Lamellated (pacinian) corpuscles (PC) detect coarse touch inner core, leading to a nerve impulse. X40. H&E. or pressure and are large oval structures, frequently 1 mm in The arrector pili muscle, a small bundle of smooth mus- % A generally long period of mitotic activity and growth cle cells, extends from the midpoint of the fibrous sheath to the (anagen), dermal papillary layer (Figure 18–13a). Contraction of these % A brief period of arrested growth and regression of the muscles pulls the hair shafts to a more erect position, usually hair bulb (catagen), and when it is cold in an effort to trap a layer of warm air near % A final long period of inactivity (telogen) during which the skin. In regions where hair is fine, contraction of arrector the hair may be shed. pili muscles is seen to produce tiny bumps on the skin surface At the beginning of the next anagen phase, epidermal (“goose bumps”) where each contracting muscle distorts the stem cells located in small bulge of the external root sheath attached dermis. near the arrector pili muscle produce progenitor cells for the As mentioned earlier hairs grow asynchronously, cycli- matrix of a new hair bulb. Hair growth on the face and pubis cally, and at different rates in different regions of the body. The is strongly influenced by sex hormones, especially androgens, hair growth cycle has three major phases: and begins at puberty.  Nails 377 FIGURE 18–13 Hair. C H A P T E R Shaft 1 8 Connective Skin Nails tissue root sheath Hair follicle Epithelial tissue root sheath Medulla Cuticle Cortex Medulla Arrector Matrix Cortex pili muscle Hair follicle Connective tissue root sheath Epithelial tissue Root b root sheath Matrix Hair bulb Hair papilla a c All types of body hair have a similar composition and form in epithelial and connective tissue sheaths. Cells of the hair hair follicles derived from the epidermis but extending deep bulb matrix proliferate, take up melanin granules, and undergo into the dermis. (a) The diagram shows major parts of a hair keratinization to differentiate as the three concentric layers of and its follicle, including vascularized, nutritive hair dermal the hair. X70. H&E. papilla and the arrector pili muscle that pulls the hair erect. (c) The outermost layer of the hair is the thin cuticle, com- (b) A longitudinal section of a hair root and bulb shows the posed of shingle-like cells, shown in this SEM of a hair shaft matrix, medulla and cortex in the root and the surrounding emerging at the stratum corneum. X260. ❯❯ MEDICAL APPLICATION ❯ NAILS Loss of hair to produce baldness or alopecia results A similar process of keratinization also produces the nails, from a complex combination of genetic and hormonal which are hard plates of keratin on the dorsal surface of each factors that is not well understood. Arresting mitotic distal phalanx (Figure 18–15). The proximal part of the nail activity in the hair matrix during cancer chemotherapy is the nail root and is covered by a fold of skin, from which disrupts both the function and the structural integrity the epidermal stratum corneum extends as the cuticle, or of hair follicles and usually leads to rapid, reversible eponychium. The nail plate is bound to a bed of epidermis, alopecia. the nail bed, which contains only the basal and spinous epi- dermal layers. 378 CHAPTER 18 Skin FIGURE 18–14 Layers of a hair and its follicle. BV CTS CTS CTS ERS ERS CO IRS ERS IRS M G G CO CU CO M CU IRS DP CB a b c (a) The base of a hair follicle sectioned obliquely shows (b) A hair root sectioned more transversely shows the same the vascularized dermal papilla (DP) continuous with the layers of the follicular sheath, but the layers of the hair root surrounding connective tissue sheath (CTS). The papilla is are now seen to include the medulla (M), cortex (CO), and cuti- enclosed by the deepest part of the epithelial sheath, which cle (CU). Other labels are like those of part (a). X140. H&E. is continuous with both the internal root sheath (IRS) and (c) SEM of a similar specimen gives a different perspective external root sheath (ERS). Both of these layers are in turn on these layers, including the shingle-like nature of the thin continuous with the stratified epidermis. Just outside the cuticle surface (CU), and the small blood vessel (BV) and ERS is the glassy membrane (G) that is continuous with the collagen bundles (CB) near the surrounding connective tissue basement membrane of the epidermis. The epithelial cells sheath (CTS). Other labels are like those of (a). X2600. (keratinocytes) around the papilla proliferate and differenti- (Figure 18–14c, with permission, from Kessel RG, Kardon ate as the root of the hair itself. Above the papilla, only the RH. Tissues and Organs: A Text-Atlas of Scanning Electron cortex (CO) of the hair is clearly seen in this section. X140. Microscopy. San Francisco, CA: W.H. Freeman & Co.; 1979.) H&E. The nail root forms from the nail matrix in which cells ❯ SKIN GLANDS divide, move distally, and become keratinized in a process somewhat similar to hair formation but without keratohyaline Sebaceous Glands granules. The nail root matures and hardens as the nail plate Sebaceous glands are embedded in the dermis over most of (Figure 18–15). Continuous growth in the matrix pushes the the body, except in the thick, glabrous skin of the palms and nail plate forward over the nail bed (which makes no contri- soles. There is an average of about 100 such glands per square bution to the plate) at a rate of about 3 mm/mo for fingernails centimeter of skin, but the frequency increases to 400-900/cm2 and 1 mm/mo for toenails. The distal end of the plate becomes in the face and scalp. Sebaceous glands are branched aci- free of the nail bed at the epidermal fold called the hyponych- nar glands with several acini converging at a short duct ium. The nearly transparent nail plate and the thin epithe- that usually empties into the upper portion of a hair follicle lium of the nail bed provide a useful window on the amount (Figure 18–16). A hair follicle and its associated sebaceous of oxygen in the blood by showing the color of blood in the glands make up a pilosebaceous unit. The stem cell niche dermal vessels. of the follicle’s bulge region also forms the progenitor cells of  Skin Glands 379 FIGURE 18–15 Nails. C H A P T E R Free edge Nail groove Phalanx (finger bone) Nail body Nail fold Nail matrix 1 8 Lunula Eponychium (cuticle) Nail root Skin Skin Glands Nail bed Hyponychium Nail plate Dermis a b Epidermis PNF DNM E NR VNM NP NB D c Nails are hard, keratinized derivatives formed in a process or cuticle. The nail root (NR), the most proximal region of the similar to that of the stratum corneum and hair. (a) Surface view nail plate (NP), is formed like the hair root by a matrix of prolif- of a finger shows the nail’s major parts, including the crescent- erating, differentiating keratinocytes. These cells make up the shaped white area called the lunula, which derives its color from dorsal nail matrix (DNM) and ventral nail matrix (VNM), which the opaque nail matrix and immature nail plate below it. contribute keratinized cells to the nail root. The mature nail (b) A diagrammatic sagittal section includes major internal plate remains attached to the nail bed (NB), which consists details of the growing nail and the hyponychium where the free of basal and spinous epidermal layers over dermis (D), but is end of the nail plate is bound to epidermis. pushed forward on this bed by continuous growth in the nail matrix. X100. Mallory trichrome. (c) A sagittal section from a finger shows the proximal nail fold (PNF) and its epidermal extension, the eponychium (E) 380 CHAPTER 18 Skin the associated sebaceous glands. In certain hairless regions, Pale-staining clear cells produce the sweat, having such as the penis, clitoris, eyelids, and nipples, sebaceous ducts abundant mitochondria and microvilli to provide large open directly onto the epidermal surface. surface areas. Interstitial fluid from the capillary-rich The acini of sebaceous glands are the classic example of dermis around the gland is transported through the clear holocrine secretion. They have a basal layer of flattened epi- cells, either directly into the gland’s lumen or into inter- thelial cells on the basal lamina, which proliferate and are cellular canaliculi that open to the lumen. displaced centrally, undergoing terminal differentiation as Dark cells filled with strongly eosinophilic granules large, lipid-producing sebocytes filled with small fat droplets (Figure 18–18a) line most of the lumen and do not (Figure 18–17). Their nuclei shrink and undergo autophagy contact the basal lamina (Figure 18–19). The gran- along with other organelles, and near the duct the cells disin- ules undergo merocrine secretion to release a poorly tegrate, releasing the lipids as the main secretory product. This understood mixture of glycoproteins with bactericidal product, called sebum, gradually covers the surfaces of both activity. the epidermis and hair sha%s. Myoepithelial cells on the basal lamina (Figure 18–19) Sebum is a complex mixture of lipids that includes wax contract to move the watery secretion into the duct. esters, squalene, cholesterol, and triglycerides that are hydro- The ducts of eccrine sweat glands have two layers of lyzed by bacterial enzymes a%er secretion. Secretion from more acidophilic cells filled with mitochondria and having cell sebaceous glands increases greatly at puberty, stimulated pri- membranes rich in Na+, K+-ATPase. These duct cells absorb marily by testosterone in men and by ovarian and adrenal Na+ ions from the secreted water to prevent excessive loss of androgens in women. Sebum helps maintain the stratum cor- this electrolyte. At the epidermis each duct merges with the neum and hair sha%s and exerts weak antibacterial and anti- stratum basale and sweat flow continues in a spiraling channel fungal properties. through the five epidermal strata to an excretory sweat pore in the skin surface (Figures 18–2a and 18–16). Sweat quickly ❯❯ MEDICAL APPLICATION evaporates upon release, cooling the skin and the blood pres- ent there. Eccrine sweat glands also function as auxiliary Acne vulgaris is an inflammatory disorder of the piloseba- excretory organs, eliminating small amounts of nitrogenous ceous unit, which can be expected to occur during adoles- waste and excess salts. cence. It involves excessive keratinization within this unit Apocrine sweat glands are largely confined to skin of and excess sebum production, both of which contribute to the axillary and perineal regions. Their development depends the blockage of ducts in the follicle. Anaerobic bacteria, on sex hormones and is not complete and functional until a%er typically Propionibacterium acnes, grow in the accumulated puberty. The secretory components of apocrine glands have sebum, leading to localized inflammation and neutrophil much larger lumens than those of the eccrine glands (Figure infiltration. The resulting enlarged follicle is called a 18–18) and consist of simple cuboidal, eosinophilic cells with comedone. numerous secretory granules that also undergo exocytosis. Thus the glands are misnamed: their cells show merocrine, not apocrine, secretion. The ducts of apocrine glands are similar to those of the Sweat Glands eccrine glands, but they usually open into hair follicles at the epidermis (Figure 18–16) and may contain the protein-rich Sweat glands develop as long epidermal invaginations embed- product. The slightly viscous secretion is initially odorless but ded in the dermis (see Figure 18–1). There are two types of may acquire a distinctive odor as a result of bacterial activ- sweat glands, eccrine and apocrine, with distinct functions, ity. The production of pheromones by apocrine glands is distributions, and structural details. well established in many mammals and is likely in humans, Eccrine sweat glands (Figures 18–16 and 18–18a) are although in a reduced or vestigial capacity. Apocrine sweat widely distributed in the skin and are most numerous on the glands are innervated by adrenergic nerve endings, whereas foot soles (620/cm2). Collectively the 3 million eccrine sweat eccrine sweat glands receive cholinergic fibers. glands of the average person approximately equal the mass of a kidney and produce as much as 10 L/d, a secretory rate far exceeding that of other exocrine glands. Sweating is a physi- ❯❯ MEDICAL APPLICATION ologic response to increased body temperature during physi- The sweat of infants with cystic fibrosis (CF) is often cal exercise or thermal stress and is the most effective means of salty and is commonly taken as indicative of this genetic temperature regulation of humans. disease. CF patients have defects in a transmembrane Both the secretory components and ducts of eccrine conductance regulator (CFTR) of epithelial cells that lead sweat glands are coiled and have small lumens. The secre- to disruptive accumulations of thick mucus in the respira- tory part is generally more pale-staining than the ducts tory and digestive tracts. Failure to remove salt from and has stratified cuboidal epithelium with three cell types sweat is related to the same genetic defect. (Figure 18–19):  Skin Glands 381 FIGURE 18–16 Glands of skin. C H A P T E R 1 8 Sweat Skin includes three major types of exocrine glands. Seba- Skin Skin Glands pore ceous glands are usually part of a pilosebaceous unit with a hair follicle and secrete oily sebum into the space around Sweat gland duct the hair root. Thermoregulatory eccrine sweat glands empty their secretion onto the skin surface via sweat pores. Apocrine sweat glands secrete a more protein-rich Hair follicle sweat into the follicles of hair in skin of the axillae and Sebaceous perineum. gland Merocrine sweat gland Arrector pili muscle Apocrine sweat gland FIGURE 18–17 Sebaceous glands. H S S D S D S D C a b Sebaceous glands secrete a complex, oily mixture of lipids then disintegrating near the ducts (D) opening at the hair (H) called sebum into short ducts that in most areas open into shaft. X122. H&E. hair follicles. Sebum production is the classic example of holo- (b) A micrograph shows the gland’s capsule (C) and differ- crine secretion, in which the entire cell dies and contributes to entiates sebocytes (S) at higher magnification. Proliferation the secretory product. (a) A section of a pilosebaceous unit of the small progenitor cells just inside the capsule continu- shows acini composed of large sebocytes (S), which undergo ously forces sebum into the ducts; myoepithelial cells are not terminal differentiation by filling with small lipid droplets and present. X400. H&E. 382 CHAPTER 18 Skin FIGURE 18–18 Eccrine and apocrine sweat glands. H S D S S D a b (a) Histologically eccrine glands have small lumens in the (b) Apocrine sweat glands, which produce a more protein-rich secretory components (S) and ducts (D), both of which have secretion with pheromonal properties, are characterized by an irregular stratified cuboidal appearance. Both clear and secretory portions (S) with lumens much larger than those acidophilic cells are seen in the stratified cuboidal epithelium of eccrine glands. Their ducts (D) open into hair follicles (H) of the secretory units. rather than to the epidermal surface. Both X200. Mallory trichrome. FIGURE 18–19 Eccrine sweat gland secretory cells. L D TEM of these important thermoregulatory structures reveals D three cell types in their secretory portions. Myoepithelial cells (M) are present at the basal lamina (BL) to propel sweat into the duct. Irregular pyramidal cells called dark cells (D) border the lumen (L) and are filled with the electron- IC dense, eosinophilic secretory granules that release bacte- ricidal peptides and other components of innate immunity. Columnar clear cells (C) on the basal lamina rapidly trans- port water from interstitial fluid in the capillary-rich dermis directly into the lumen or into intercellular canaliculi (IC) continuous with the lumen. Na+ ions are recovered from this fluid through the action of cells in the ducts. X6500. C C M M C BL  Skin Repair 383 ❯ SKIN REPAIR wound healing, whether initiated surgically or accidentally, involves several overlapping stages that vary in duration with C H A P T E R Skin has a good capacity for repair, which is important in this the size of the wound (Figure 18–20). In the first phase blood exposed and easily damaged organ. The process of cutaneous from cut vessels coagulates in the wound, releasing polypep- FIGURE 18–20 Major stages of cutaneous wound healing. 1 8 Wound Blood clot Skin Skin Repair Epidermis Dermis Macrophages Fibroblast Neutrophils Leukocyte 1 Cut blood vessels bleed into the wound. 2 Blood clot forms, and leukocytes clean wound. Blood clot Scab Macrophages Regenerated epidermis Granulation tissue Regrowth of Scar tissue blood vessel (fibrosis) Fibroblast Fibroblast 3 Blood vessels regrow, and granulation tissue forms. 4 Epithelium regenerates, and connective tissue fibrosis occurs. Skin repair occurs in overlapping stages shown here schemati- Under the influence of growth factors and hydrolytic cally. The process begins with blood quickly clotting at the enzymes released in part from macrophages, fibroblasts wound site, releasing platelet-derived growth factors and other proliferate and produce much new collagen to form “granulation substances (1). Macrophages and neutrophils enter the wound tissue” containing many new, growing capillaries (3). The as inflammation begins, and epithelial cells from the cut edges epidermis gradually reestablishes continuity over the wound of the stratum basale begin to migrate beneath and through site, but excessive collagen usually remains in the dermis as the blood clot (2). scar tissue (4). 384 CHAPTER 18 Skin tide growth factors and chemokines from the disintegrating from their binding sites in ECM proteoglycans. Matrix metal- platelets. Neutrophils and macrophages undergo diapede- loproteinases and other proteases from the migrating cells and sis locally and remove bacteria and debris from the wound. macrophages facilitate cell migration. These are major events of inflammation that typically lasts Proliferating fibroblasts and newly sprouted capillaries 2 to 3 days. produce new collagen-rich, well-vascularized tissue in the Before this phase is completed, epithelialization begins dermis called granulation tissue, which gradually replaces as cells of the epidermal basal layer remove their desmosomes the blood clot (Figure 18–20). In the final stage the epidermis and hemidesmosomes and migrate laterally beneath the blood reestablishes continuity but has lost the ability to form new clot that