Development of the Skin and Its Derivatives


Summary

The skin, or integument, consists of two layers: the epidermis and the dermis . The epidermis is formed mainly by the embryonic surface ectoderm, although it is also colonized by melanocytes (pigment cells), which are derived from neural crest cells, and by Langerhans cells , which are immune cells of bone marrow origin. The dermis of the trunk is a mesodermal tissue. The ventral dermis is derived mainly from the somatic layer of the lateral plate mesoderm, whereas the dorsal dermis is derived from the dermamyotome subdivision of the somites (covered in Chapter 8 ). The dermis of the face is formed from neural crest cells (covered in Chapter 4, Chapter 17 ).

After neurulation, the surface ectoderm, originally consisting of a single layer of cells, forms an outer layer of simple squamous epithelium called the periderm . The inner layer is now called the basal layer . In the 11th week, the basal layer forms a new intermediate layer between itself and the periderm. The basal layer is now called the stratum germinativum ; this layer will continue to produce the epidermis throughout life. By the 21st week, the intermediate layer is replaced by the three definitive layers of the outer epidermis: the inner stratum spinosum , the middle stratum granulosum , and the outer stratum corneum , or horny layer . The cells of these layers are called keratinocytes because they contain the keratin proteins characteristic of the epidermis. The layers of the epidermis represent a maturation series: keratinocytes produced by the stratum germinativum differentiate as they pass outward to form the two intermediate layers and the flattened, dead, keratin-filled mature keratinocytes of the horny layer, which are finally sloughed from the surface of the skin. As the definitive epidermis develops, the overlying periderm is gradually shed into the amniotic fluid. Fetal skin cells shed into the amniotic fluid, called amniocytes , can be obtained from the amniotic fluid by amniocentesis and cultured to form amniotic stem cells , which have potential therapeutic value (covered in Chapter 6 ).

The dermis contains most of the tissues and structures of the skin, including its blood vessels, nerves, and muscle bundles, and most of its sensory structures. The superficial layer of the dermis develops projections called dermal papillae , which interdigitate with downward projections of the epidermis called epidermal ridges .

A number of specialized structures develop within the surface ectoderm, including hairs, a variety of epidermal glands, nails, and teeth (covered in Chapter 17 ). Hair follicles originate as rod-like downgrowths of the stratum germinativum into the dermis. The club-shaped base of each hair follicle is indented by a hillock of dermis called the dermal papilla , and the hair shaft is produced by the germinal matrix of ectoderm that overlies the dermal papilla. Various types of epidermal glands also arise as diverticula of the epidermis. Some bud from the neck of a hair follicle; others bud directly downward from the stratum germinativum. The four principal types of epidermal glands are the sebaceous glands , which secrete the oily sebum that lubricates the skin and hair; the apocrine sweat glands , found in the axillae, the pubic region, and other specific areas of skin that secrete odorous substances; the accrine sweat glands , which are widely distributed over the surface of the skin, where they function in body cooling; and the mammary glands . The primordia of the nails arise at the distal tips of the digits and then migrate around to the dorsal side. The nail plate grows from a specialized stratum germinativum located in the nail fold of epidermis that overlaps the proximal end of the nail primordium.

Clinical Taster

You are a pediatrician following a 3½-year-old girl with chronic constipation that started around the beginning of “potty training.” You get a message from your answering service that the girl’s mother called during the night from the emergency room. Apparently, they rushed the girl to the hospital in the late evening, when they found that she had rectal prolapse (protrusion of the rectum out through the anus) after straining to stool.

You see the girl with her mother later that day for follow-up. The girl was seen in the emergency room by a surgeon, who had reduced the prolapsed rectum without surgery and prescribed an enema and stool softeners. The surgeon had mentioned to the family that their pediatrician would talk to them about conditions like cystic fibrosis that can be associated with rectal prolapse and would arrange to test for such conditions.

While examining the toddler’s abdomen for impacted stool, you notice that she has pale, velvety skin and an unusual number of bruises and atrophic scars (widened paper-like scars) on her shins. The mother reminds you that the girl was born 1 month premature after her “water broke early,” and that she was a “floppy” baby who starting walking late. Her mother states that the girl inherited her father’s “double-jointedness,” and the girl proceeds to demonstrate just how flexible her joints are ( Fig. 7.1 ). You also find her skin to be hyperextensible.

Fig. 7.1, Demonstration of Painless Hyperflexibility of the Right Third Metacarpal-Phalangeal Joint in a Child

You tell the mother that testing for cystic fibrosis is certainly reasonable, but that you suspect the diagnosis of Ehlers-Danlos syndrome (EDS) , which is a hereditary connective tissue disorder. EDS is actually a group of disorders caused by mutations in several genes involved in the formation of structural components of skin and joints including the COLLAGEN type I, II, and V genes. These conditions vary in severity and in the organ systems affected. You refer the patient for genetic evaluation and testing to determine the molecular cause in order to guide appropriate therapy. You reassure the mother that, with this information, her daughter’s condition can be managed by restricting certain types of activities and by monitoring for more significant complications like dilation of the aortic root for certain forms of the condition.

Timeline

Origin of Epidermis and Dermis Of Skin

Surface Ectoderm Forms Epidermis

The surface ectoderm covering of the embryo consists initially of a single layer of cells. After neurulation in the fourth week, the surface ectoderm produces a new outer layer of simple squamous epithelium called the periderm ( Fig. 7.2A ). The underlying layer of cells is now called the basal layer and is separated from the dermis by the basement membrane containing proteins such as collagen, laminin, and fibronectin. The cells of the periderm are gradually sloughed into the amniotic fluid. The periderm is normally shed completely by the 21st week, but in some fetuses it persists until birth, forming a “shell” or “cocoon” around the newborn infant that is removed by the physician or shed spontaneously during the first weeks of life. These babies are called collodion babies .

Fig. 7.2, Differentiation of the Ectoderm Into the Primitive Epidermis

In the 11th week, proliferation of the basal layer produces a new intermediate layer just deep to the periderm ( Fig. 7.2B ). This layer is the forerunner of the outer layers of the mature epidermis. The basal layer, now called the germinative layer or the stratum germinativum , constitutes the layer of stem cells that will continue to replenish the epidermis throughout life. The cells of the intermediate layer contain the keratin proteins characteristic of differentiated epidermis; therefore, these cells are called keratinocytes .

During the early part of the fifth month, at about the time that the periderm is shed, the intermediate layer is replaced by the three definitive layers of the outer epidermis: the inner stratum spinosum (or spinous layer ), the middle stratum granulosum (or granular layer ), and the outer stratum corneum (or horny or cornified layer ) ( Figs. 7.3, 7.4 ). This transformation begins at the cranial end of the fetus and proceeds caudally. The layers of the epidermis represent a maturational series: presumptive keratinocytes are constantly produced by the stratum germinativum, they differentiate as they pass outward to the stratum corneum, and, finally, they are sloughed from the surface of the skin.

Fig. 7.3, Differentiation of the Mature Epidermis Light Micrographs The periderm (P) is sloughed during the fourth month and normally is absent by week 21. The definitive epidermal layers, including the stratum germinativum (SGE) , stratum spinosum (SS) , stratum granulosum (SGR) , and stratum corneum (SC) , begin to develop during the fifth month and become fully differentiated postnatally.

Fig. 7.4, Differential Expression of Keratins and Envelope Proteins During Differentiation of the Skin

The cells of the stratum germinativum are the only dividing cells of the normal epidermis. These cells contain a dispersed network of primary keratin (Krt) filaments specific to this layer, such as Krt5 and Krt14, and are connected by cell-to-cell membrane junctions called desmosomes . Together with adherens junctions, desmosomes provide a tight, impervious barrier resistant to water uptake or loss and infection. In addition, desmosomes help to distribute force evenly over the epidermis.

As the cells in the stratum germinativum move into the overlying stratum spinosum (4 to 8 cells thick; see Fig. 7.4 ), the Krt5 and Krt14 intermediate filaments are replaced by two secondary keratin proteins, Krt1 and Krt10. These are cross-linked by disulfide bonds to provide further strength. In addition, cells in the stratum spinosum produce the envelope protein , involucrin.

As the cells in the stratum spinosum move into the stratum granulosum, they produce other envelope proteins , such as loricrin and envoplakin, which, together with the envelope protein involucrin, line the inner surface of the plasma membrane. The enzyme transglutaminase cross-links the envelope proteins. Another protein called filaggrin is produced at this time. Filaggrin aggregates with the keratin filaments to form tight bundles, helping to flatten the cell. Lipid-containing granules ( lamellar granules ) that help seal the skin are also produced. Finally, in the process called cornification , lytic enzymes are released within the cell, metabolic activity ceases, and enucleation occurs, resulting in loss of cell contents, including the nucleus. Consequently, the keratinocytes that enter the stratum corneum are flattened, scale-like, and terminally differentiated keratinocytes, or squames .

In the Research Lab

Stem Cells in Integument

The skin is the largest organ of the body. It undergoes self-renewal every 4 weeks and, therefore, rapid turnover of cells occurs. Consequently, the skin requires a large number of stem cells , which, owing to their superficial location in the body, can be easily used therapeutically to regenerate the skin and its derivatives. Moreover, stem cells have the potential to regenerate other organs.

Several clearly defined populations of stem cells are found within the skin ( Fig. 7.5 ). These include:

  • Basal stem cells, which give rise to the interfollicular skin (i.e., the skin between the hair follicles)

  • The bulge, which gives rise to the hair follicle but can also give rise, after severe wounding, to the interfollicular epidermis and the sebaceous glands providing a transient repair until the basal stem cells can fully regenerate the skin. Therefore, skin grafting is not required after tissue damage (e.g., burns) if hair follicles remain intact

  • Cells at the base of the sebaceous gland, which generate the sebocytes

Fig. 7.5, Structure of a Hair Follicle Showing the Bulge and the Layers of the Hair Shaft Stem cells in the bulge, stratum germinativum (SGE) , and sebaceous gland are shown in green. SC, Stratum corneum; SGR, stratum granulosum; SS, stratum spinosum.

These three populations of stem cells are characterized by the expression of p63 (a transcription factor also called tumor protein p73-like), E-cadherin, and keratins Krt5 and Krt14. Although differentiation of the three stem cell populations differs in terms of their requirements for hedgehog (Hh) and Wnt signaling, in all cases stem cell differentiation requires activation of notch signaling. This is illustrated for the skin in Fig. 7.4 , which shows that notch signaling promotes the onset of differentiation by inducing p21 (a cell cycle inhibitor) and Krt1/10 expression, while inhibiting expression of stem cell components and regulators such as Krt5/14 and p63. Notch signaling also inhibits Wnt and Hh signaling, as well as expression of late differentiation markers (e.g., loricrin). In addition, a new population of multipotential cells, known as skin-derived precursor (SKP) cells, has been identified. In vitro derivatives include both epidermal and mesenchymal lineages, such as neuronal cells, glia, adipocytes, smooth muscle cells, and chondrocytes. SKP cells are thought to be derived from neural crest cells (as are adult neural crest stem cells in the gut; see Chapter 14, Chapter 4 ); their numbers are highest in the fetus and decline postnatally.

Recent work has focused on the induction of pluripotent stem cells from somatic cells. It has been shown that human dermal fibroblasts and keratinocytes can be reprogrammed to be pluripotent (i.e., capable of giving rise to many different cell types) after a combination of factors are added (e.g., Oct4, Sox2, nanog, Lin28), providing additional strategies for regenerative medicine (also see Chapter 5 on iPS cells).

Early Embryo Does Not Scar

In the first two trimesters, embryonic skin does not scar following wounding, and in adults, different epithelia have intrinsic differences in their potential to scar (e.g., oral cavity versus abdominal skin). In the embryo, this is partly due to the absence of the immune system, but recent studies have also revealed that scarring potential is related to developmental changes in the fibroblast population in the dermis of the skin. The early dermis is populated by engrailed-negative fibroblasts and these cells do not produce a matrix conducive to scarring. In contrast, the older dermis is populated by engrailed-positive cells arising from the dermamyotome of the somite. These engrailed-positive fibroblasts produce collagens I and III, key components of scar tissue. Cell transplantation experiments have revealed that scarring is an intrinsic property of the engrailed-positive fibroblasts.

Other Types of Epidermal Cells

In addition to keratinocytes, the epidermis contains a few types of less abundant cells, including melanocytes, Langerhans cells, and Merkel cells. As covered in Chapter 4 , the pigment cells, or melanocytes , of the skin differentiate from neural crest cells that detach from the neural tube in the sixth week and reach the epidermis shortly after ( Fig. 7.8A ). Although all melanocytes are derived from neural crest cells, they can develop in two distinct ways. Some melanocyte precursors arise directly from the neural tube and migrate dorsally into the skin, whereas others arise from Schwann cell precursors (SCP, which are formed from neural crest cells that migrate ventrally) associated with the nerves innervating the skin (also see Chapter 10 ).

Fig. 7.8, Specialized Cells of the Epidermis (A) Melanocytes (M) first appear in the embryonic epidermis during the sixth and seventh weeks. (B) Langerhans cells (L) migrate into the epidermis from the bone marrow, starting in the seventh week. F, Hair follicle.

Melanocytes represent between 5% and 10% of the cells of the epidermis in the adult. In the 10th week, many melanocytes become associated with developing hair follicles (covered later in the chapter), where they function to donate pigment to the hairs.

Melanocytes function as a sunscreen, protecting the deeper layers of the skin from solar radiation, which can cause not only sunburn but also, in the long run, cancer. Unfortunately, melanocytes themselves also produce tumors. Most of these remain benign, but sometimes they give rise to the highly malignant type of cancer called melanoma .

In the Clinic

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