Structure and Function of Newborn Skin

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Structure and Function of Newborn Skin

Anthony J. Mancini, Leslie P. Lawley

Introduction

The skin of the newborn serves a pivotal role in the transition from the aqueous intrauterine environment to extrauterine terrestrial life and is integral to the vital functions of mechanical protection, thermoregulation, cutaneous immunosurveillance, and maintenance of a barrier that prevents insensible loss of body fluids. The anatomy and function of skin are most easily understood by dissecting the individual compartments (stratum corneum, epidermis, dermoepidermal junction (DEJ), dermis and subcutaneous tissue) and their component cell types. Specialized structures found within these compartments, such as pilosebaceous units, sweat glands, nerves, and vascular networks, play an essential role both anatomically and functionally in cutaneous homeostasis in the neonate. The anatomy of these compartments and structures of the skin, and the physiologic processes involved in their functions, are the focus of this chapter.

Human skin consists of three layers: epidermis, dermis, and subcutaneous fat (Fig. 2.1). All elements of skin are derived from either ectoderm or mesoderm, the former giving rise to the epidermis and other cutaneous epithelial components.1 A brief description of fetal skin development is helpful in understanding the structure and function of newborn skin, and is incorporated into some of the following discussions of the various compartments and structures. A more thorough review of cutaneous embryology is the focus of Chapter 1.

Stratum corneum and epidermis

The most obvious clinical difference between the skin of the term newborn and that of an adult is the presence of the moist, greasy, yellow-white substance called vernix caseosa, which is a coating comprised of a combination of sebaceous gland secretions, desquamated skin cells, and shed lanugo hairs.2,3 The vernix caseosa has an important role in maintaining hydration and pH balance, and preventing infection during the first few days of life.4,5 Certain components of the innate immune system, termed antimicrobial polypeptides (see ‘Cutaneous immunosurveillance, Langerhans’ cells, and cytokines‘, below), have been isolated in the vernix and probably play an important role in surface defense in the newborn.4,6,7 This coating persists for the first several days of postnatal life, eventually disappearing completely to reveal the more typical, moderately dry newborn skin. Vernix provides water-binding free amino acids, which may help to facilitate the neonate’s adaptation from the amniotic fluid intrauterine milieu to the ambient dryness of the extrauterine environment.8 Vernix-based topical creams have been investigated for treatment of epidermal wounds and augmentation of barrier repair in infants.9

The structure of term newborn skin is histologically similar to that of older individuals, whereas premature infant skin reveals several unique features that have increased our understanding of fetal skin development. The outermost compartment of the skin, the epidermis, arises from surface ectoderm and at about the 3rd week of fetal life, consists of a single layer of undifferentiated cells that becomes two-layered by around 4 weeks.10 The outer layer of cells, the periderm, is found only in developing skin and is transiently present, eventually undergoing a series of apoptotic cellular events as the epidermis becomes multilayered and the stratum corneum, the outermost layer of flattened, non-nucleated skin cells, is forming.11 By 24 weeks’ gestation, the periderm is largely absent,10,11 and the epidermis shows considerable progressive maturation, which is largely complete by 34 weeks.12 A thin, hydrophobic layer of the periderm may persist for several days postnatally and may participate in protective and thermoregulatory functions.13

The epidermis is a stratified epithelium, the number of cell layers varying between different body regions. The various layers, from the dermal side toward the skin surface, are termed the stratum basale, stratum spinosum, stratum granulosum, and stratum corneum. In areas of thicker skin, such as the palms and soles, the stratum lucidum is interposed between the granular and corneal layers. These epidermal layers are shown in Figure 2.2.

Individual cells within the epidermis are referred to as keratinocytes, so named for the intermediate-sized filament proteins (keratins) that are synthesized within them. Keratins (K) are the major structural proteins of the epidermis and its appendages, constituting up to 85% of the total protein of fully differentiated epidermal keratinocytes.14 They have been divided into types I and II based on their acidic or basic nature, respectively, and are frequently configured in specific pairs of a type I and a type II protein as obligatory heteropolymers.15 Terminal differentiation of the epidermis involves the sequential expression of different proteins, including the keratins, in the basal and spinal layers.16 An important function of the keratins is imparting mechanical integrity to epithelial cells. Mutations in the genes encoding these proteins have been confirmed as the basis of several inherited skin defects, such as the simplex form of the mechanobullous disease, epidermolysis bullosa.14 The profiles of epithelial cell keratins change during gestation: K5 and K14 (basal cell keratins) are present from 8 weeks’ gestation, K1 and K10 (differentiation-specific keratins) begin to be expressed between 9 and 10 weeks’ gestation, and some keratins (such as K8 and K19) are present in the fetus but not in adult epidermis.17

The stratum basale consists of a single layer of cells, the basal portions of which are in contact with the dermis and contribute to the DEJ. The cells of the basal layer are cuboidal to columnar in shape and are anchored to the underlying dermis by cytoplasmic processes. The stratum basale has an undulating surface inferiorly, forming projections called rete ridges, which lie interposed between the dermal papillae of the superficial (papillary) dermis (Fig. 2.3). The basal cell layer contains cells that eventually replace those continually lost from the epidermis through terminal differentiation, maturation and desquamation. Interspersed among the cells in the basal cell layer are the dendritic, pigment (or melanin)-producing cells (melanocytes), which are discussed in more detail below (‘Melanocytes and pigmentation of the skin’).

The stratum spinosum consists of the cells between the stratum basale and the stratum granulosum and forms the bulk of mammalian epidermis. The keratinocytes in this layer are polyhedral in shape and have numerous tiny, spiny projections spanning the intercellular space between contiguous cells.18 These projections are composed ultrastructurally of desmosomes, which form communication junctions between the cells. Keratinocytes of the spinous layer become larger, flatter, and more desiccated as they progress from the basal layer toward the skin surface. Also present in this layer are Langerhans’ cells, bone marrow-derived cells that are involved in cutaneous immunosurveillance through antigen processing and presentation (see ‘Cutaneous immunosurveillance, Langerhans’ cells and cytokines‘, below).

The stratum granulosum comprises a thin layer of darkly stained keratinocytes at the outermost surface of the stratum spinosum. The dark appearance of these cells is due to the presence of keratohyalin granules, which are composed of an electron-dense protein (profilaggrin) and keratin intermediate filaments.19 Profilaggrin is subsequently converted to filaggrin, a protein involved in the aggregation and disulfide bonding of keratin filaments,20,21 and it has been suggested that keratohyalin serves to form a matrix that provides structural support by linking keratin filaments to one another.18 Filaggrin eventually is degraded into free amino acids, including histidine and glutamine, which are further metabolized into urocanic acid (UCA) and 2-pyrrolidone-5-carboxylic acid (PCA). These free amino acids and their by-products constitute a significant component of natural moisturizing factor (NMF), which is retained in non-nucleated keratized cells (corneocytes) and helps maintain epidermal hydration.22 The granular cell layer is also where lamellar bodies (lamellar granules, Odland bodies, membrane-coating granules) are produced.23 These intracellular organelles participate in the formation of the epidermal permeability barrier through the production and discharge of lipid substances into the intercellular corridors of the stratum corneum. Defective lipid transport in lamellar bodies caused by mutations in ABCA12 underlies the severe skin disorder known as harlequin ichthyosis.24 In areas of thicker skin, such as the palms and soles, the stratum lucidum is present as a layer with a clear hyaline appearance. At this level one can visualize transitional cells that exhibit marked degeneration of the nucleus and other organelles and, ultramicroscopically, keratin filaments and keratohyalin granules, which are abundant but not yet as compact as in the stratum corneum.18

The stratum corneum, or cornified layer, is composed of several layers of flattened corneocytes arranged in an overlapping fashion. The thickness of this layer varies by body region, being thinnest on the face (especially over the eyelids) and genitalia, and thickest on the palms and soles. It is now widely accepted that the epidermal permeability barrier resides in the stratum corneum and serves the vital functions of preventing excessive transepidermal water loss (TEWL) and preventing penetration of a variety of substances.2529

The formation of the epidermal barrier is accomplished through the lipid secretions of lamellar bodies, which include free fatty acids, ceramides, and cholesterol. These lipids are deposited in the intercellular interstices within the stratum corneum. This arrangement has been likened to ‘bricks and mortar,’ where the corneocytes represent the bricks and the intercellular lipids represent the mortar.30 Although these lipids represent only about 10% of the dry weight of the stratum corneum31 their location and composition are vital, and cutaneous barrier function is dependent on both the generation of sufficient quantities of these lipids and their strategic secretion and organization into lamellar bilayer unit structures.29,30,3234 In fact, the epidermis is equipped with the necessary machinery to autonomously regulate its lipid-synthesis apparatus in response to specific barrier requirements.3537 The development of a functional barrier has been shown to be closely correlated with normal ontogenesis and does not appear to be disrupted by somatic growth retardation.38 Hence, more mature infants, even those who are small for gestational age, have a competent epidermal barrier.39

The epidermis and stratum corneum in the full-term infant are well developed, and the barrier properties are excellent.40 Conversely, premature infants have greater skin permeability and a more poorly functioning barrier. Histologically, the term infant has a well-developed epidermis, which is several layers thick, and a well-formed stratum corneum.2,12 This maturity is lacking in preterm infants.4044 An acceleration of skin maturation may occur postnatally in preterm infants, although in extremely low-birthweight infants (23–25 weeks’ gestational age), complete development of a fully functional barrier may require up to 8 weeks.41,42,45 Studies support the long-held notion that the shift from an aqueous to an air environment, and hence water flux, may be an important factor in this acceleration of barrier formation.46 The nuclear hormone receptors peroxisome proliferator-activated receptor (PPAR-α, -δ, -γ) and their ligands have varied roles in driving the development of the stratum corneum and permeability barrier in the fetus as well as in neonates and adults.47 Functional skin adaptation is an ongoing dynamic process involving acidification, water management and permeability barrier development throughout the first year of life and perhaps beyond. The ability to restore the epidermal barrier declines in adulthood.48,49 During the period of postnatal barrier maturation, large transepidermal water losses contribute to the morbidity of the preterm infant, and therefore a major focus of past studies has been the development of a therapeutic strategy to accelerate epidermal barrier maturation or augment its function, including the use of semipermeable membranes5053 or topical emollients.54,55 Skin surface pH is another important consideration, as acidification is vital to epidermal barrier maturation, and the ‘acid mantle’ also plays a role in maintaining bacterial and chemical resistance of the skin. While no definitive relationship between gestational age and skin pH has been confirmed, studies have shown that skin pH is higher (more alkaline) immediately after birth, and decreases (becomes more acidic) over the first few weeks of postnatal life.56 Premature infant skin and barrier maturation are discussed in more detail in Chapter 4.

In addition to the prevention of insensible water losses across the skin by the epidermal barrier, the epidermis and stratum corneum of the newborn provide important protection against toxicity from exposure to ultraviolet rays (UVR), and this protective effect may be greater for UVB than for UVA radiation.57 As previously noted, melanin is primarily responsible for UVR protection, although the ‘protein barrier’ of the stratum corneum may augment this cutaneous function.58 Epidermal lipids may also play a role in protection from UVR. Another function of the superficial skin layers is protection against microorganisms, which are blocked from invasion across the skin by an intact stratum corneum. In addition to such physical factors, the antimicrobial qualities of skin may be related to the relative dryness of the stratum corneum, the presence of skin surface lipids, and the degree of epidermal cellular differentiation.5861 Skin is also a vital participant in the process of neonatal thermoregulation (discussed in more detail later) through regulation of cutaneous blood flow and evaporative water loss.

Percutaneous absorption of substances across neonatal skin requires passage through the stratum corneum and epidermis, diffusion into the dermis, and eventual transfer into the systemic circulation. Transfer across the stratum corneum and epidermis may be through the intercellular corridors (favoring nonpolar or hydrophobic compounds) or via a transcellular route (which favors polar or hydrophilic substances).62 Hair follicles and eccrine sweat ducts may serve as diffusion shunts for certain substances (i.e. ions, polar compounds, very large molecules), which would otherwise traverse the stratum corneum slowly (because of their large molecular weight).63 The rate-limiting step of percutaneous absorption seems to be diffusion through the stratum corneum,63 and hence the effectiveness of the epidermal permeability barrier correlates inversely with percutaneous absorption. Percutaneous absorption, although continuously being explored for therapeutic applications, may contribute to systemic absorption and potential toxicity after topical application of some substances to newborn skin, especially in preterm infants or those with cutaneous damage.41 Importantly, although the barrier function of intact skin in the term infant is usually normal, the surface area-to-weight ratio is greater than in older children and adults. Caution should therefore be exercised in the use of topical agents in any newborn, with extra caution and a thorough risk–benefit analysis being employed in the case of premature infants or any neonate with a compromised skin barrier. Percutaneous absorption is discussed in more detail in Chapter 5.

Dermoepidermal junction

The dermoepidermal junction (DEJ) is an important site of attachment in skin, occurring at the interface between the basal epidermis and the papillary dermis. It appears that the various components of the DEJ are expressed in term newborn skin in a manner similar to that in adults, without apparent differences in their quantity or associations.2 For reasons that are poorly understood, however, skin appears to be more fragile during the newborn period, even in term infants, as evidenced by blisters or erosions developing in situations that do not cause blisters later in life (e.g., erosions due to diapering, sucking blisters on fingers and hands, and disease states such as bullous syphilis).

Specialized structures called ‘hemidesmosomes’ assist in anchoring the basal keratinocytes to the underlying plasma membrane. Ultrastructurally, the DEJ can be broken down into several planes, including (from the epidermal side to the dermal side) the inferior portion of the basal keratinocyte; an empty-appearing, electron-lucent clear plane known as the lamina lucida; a thin, dark, electron-dense layer known as the lamina densa; and the sublamina densa fibrillar region (Fig. 2.4).19,64 Each of these layers contains individual components that function harmoniously in concert to create cohesion between the epidermis and the underlying dermis. Defects in, or antibodies directed against, some of these components have been etiologically linked to cutaneous disease.

Major constituents of the DEJ include bullous pemphigoid (BP) antigens, α6β4 integrin, laminin-5 (laminin-332), type IV collagen, and type VII collagen. The BP antigens are large glycoproteins with both intracellular (BP antigen 1) and transmembrane (BP antigen 2) components. BP antigen 2, also known as collagen type XVII, extends from the basal keratinocyte across the lamina lucida into the lamina densa,65 and autoantibodies directed against it have been found in the sera of patients with BP, pemphigoid gestationis, mucous membrane pemphigoid, linear IgA disease, lichen planus pemphigoides, and pemphigoid nodularis.66,67 Reduced or absent expression of BP antigen 2 is found in patients with a hereditary junctional form of epidermolysis bullosa (EB) termed junctional EB-non-Herlitz, and has been described in a rare variant of EB simplex.6771

α6β4 integrin is a membrane glycoprotein component of the hemidesmosome, and defects in this integrin have been identified in a subset of patients with junctional EB in combination with pyloric atresia.7275 Laminin-5 is a glycoprotein localized mainly to the lamina densa and lower lamina lucida,76 and is also associated predominantly with hemidesmosomes.77 Mutations in the genes encoding various chains of laminin-5 have been identified in patients with the lethal (Herlitz) junctional type of EB.7881

Type IV collagen predominates in the lamina densa region, whereas type VII collagen, which is also known as the epidermolysis bullosa acquisita (EBA) antigen, is situated in the zone beneath the lamina densa. EBA antigen was so named because it was first defined by circulating autoantibodies in the sera of patients with EBA, an acquired autoimmune blistering disease.82 The dystrophic forms of inherited EB have been shown to be a result of defects in the gene encoding type VII collagen.83

Dermis and subcutaneous fat

The dermis of human skin consists primarily of connective tissues, including proteins (collagen and elastic tissue) and ground substance. This compartment lies between the epidermis superiorly and the subcutaneous fat inferiorly and forms a resilient and flexible layer that envelops the entire organism. It is divided into superficial (papillary) and deep (reticular) components, which are anatomically divided by a thin plexus of blood vessels. Although differentiation between these dermal compartments can be ascertained on the basis of the size of the collagen fiber bundles in adult skin, this criterion is less helpful in newborn skin, where there is a more gradual transition in fiber bundle size.2 Structures found within the dermis, which are discussed in different sections of this chapter, include the cutaneous appendages (pilosebaceous units, eccrine and apocrine sweat glands), as well as nerves, blood vessels, and lymphatics.

Collagen is the major constituent of mammalian dermis and accounts for approximately 75% of the dry weight of the skin.19 The collagens are a family of related, yet individually distinct, structural proteins, and in the skin, they provide tensile strength and elasticity. Types I and III collagen are the major collagens found in human dermis, and smaller amounts of types IV (a primary component of the basement membrane as noted above), V, VI, and VII are also present.84 Some 80–90% of dermal collagen is type I. Type III collagen was initially termed ‘fetal collagen’ because of its predominance in fetal tissues, where it accounts for over half of total skin collagen. However, synthesis of type I collagen accelerates during the postnatal period, and eventually, the ratio of type I to type III collagen increases, such that in adult skin it is around 5 : 1–6 : 1.85 Abnormalities in collagen synthesis or post-translational processing may result in clinical disease, including osteogenesis imperfecta and the Ehlers–Danlos syndromes.

Elastic fibers play an important role in the structure and function of skin, providing elasticity and resilience. They consist of two components: elastin, which is a connective tissue protein, and elastic fiber-associated microfibrillar component, a complex of glycoproteins.84 Elastic fibers are distributed in the papillary and reticular dermis. Fibers in the papillary dermis have been subdivided into elaunin fibers, which are oriented parallel to the DEJ, and oxytalan fibers, which connect the elaunin fibers to the DEJ.1 It has been demonstrated that elastic fibers are distributed in the term newborn dermis in a manner similar to that of the adult, albeit with a decreased elastin content in the papillary dermal bundles, and with a finer fiber diameter in the reticular dermis.2 The most widely recognized disease related to abnormalities in elastin production is cutis laxa, a heterogeneous group of disorders featuring lax skin and occasional systemic involvement in the form of hoarseness, emphysema, hernias, and diverticulae.86

The ground substance of the dermis is an amorphous material that surrounds and embeds the fibrous and cellular components found in this compartment. Glycosaminoglycans (GAGs), which are long chains of aminated sugars, and proteoglycans (PGs), which are large molecules consisting of a core polypeptide linked to GAGs, are major constituents of ground substance.1,19 Major GAGs and PGs in the dermis are chondroitin sulfate, dermatan sulfate, heparin/heparin sulfate, chondroitin 6-sulfate, and hyaluronic acid (hyaluronan).1,19,87 These components are capable of retaining large amounts of water and may also play a role in binding growth factors and providing structural support, anticoagulation, and adhesion.1,88,89 Hyaluronic acid has been demonstrated in large amounts in fetal dermis and amniotic fluid and is thought by some to be associated with the rapid wound healing without scarring that has been observed to occur in fetal wounds.90 These observations have been applied to the study of diabetic ulcers, where hyaluronic acid levels have been shown to be decreased, leading to the hypothesis that application of this substance may induce healing.91 Fibronectin is a large glycoprotein also found in the dermis and is associated with a variety of putative functions, including organization of the extracellular matrix, wound healing, attachment, and chemotaxis.1,19 More recent evidence suggests that dermal extracellular matrix components (fibronectin and chondroitin sulfate) and possibly the paucity of elastin compared with adult skin, as well as circulating amniotic stem cells, may play a role in fetal scarless healing.92

The subcutaneous fat is an important layer, playing a role in shock absorption, energy storage, and maintenance of body heat. The individual cells in the subcutaneous fat – adipocytes – form lobules that are separated by fibrous septa. The fibrous septa contain neural and vascular elements and connect deeper with the fascia of underlying skeletal muscle. In contrast, brown adipose tissue (BAT or brown fat) is a distinct type of adipose tissue, traditionally believed to be present only in newborns, that plays a vital role in neonatal thermoregulation (discussed in more detail later) through the oxidation of fatty acids.93 BAT makes up 2–6% of the neonate’s total body weight and is found primarily in the scapular region, the mediastinum, around the kidneys and adrenal glands, and in the axilla.94 The nonshivering thermogenesis that occurs in this tissue appears to be regulated by the enzyme-uncoupling protein thermogenin (more recently known as uncoupling protein 1 or UCP-1), which serves as a protonophore through the mitochondrial membrane, enabling high rates of cellular respiration and proton conductivity.95 BAT is believed to be depleted over time, although recent studies suggest that functionally active BAT is present in at least some adults.96

Pilosebaceous units, apocrine glands, and nails

Hair follicles

The earliest hair follicles begin to form at 9–12 weeks’ gestation97 primarily in a facial location, and the bulk of the remaining hairs start developing around 16–20 weeks, progressing in a cephalocaudad fashion.97,98 In some full-term infants, and especially in premature infants, the skin surface is covered with lanugo hairs, which are soft, fine hairs with limited growth potential.2 These hairs are usually shed by term, or shortly thereafter, and are replaced by vellus hairs, which are eventually replaced on the scalp by coarse terminal hairs. The growth of a hair follicle is cyclic, the stages being divided into anagen (active growth), catagen (transitional involution), and telogen (resting) phases. The typical length of each of these phases is 2–5 years, 3 days, and 3 months, respectively.98 No new hair follicles are formed after birth. The majority of hairs present at birth are synchronized in their growth phase.3,99 However, the initiation of hair production occurs in waves, such that follicles in the frontal and parietal regions of the neonate are already converting to the telogen phase, whereas occipital scalp hair progresses towards the telogen phase between 8 and 12 weeks’ postnatal age.100 This contributes to the frequent appearance of temporary occipital alopecia in young infants. The hair follicle is organized into a series of concentric cellular compartments, the details of which are beyond the scope of this chapter. The structure of a pilosebaceous unit is depicted in Figure 2.5. Longitudinally, the hair follicle can be divided into three zones: the infundibulum, extending from the opening of the follicle to the entrance of the sebaceous duct; the isthmus, extending from the entrance of the sebaceous duct to the insertion of the arrector pili muscle; and the inferior segment, which forms the remainder of the follicle from the insertion of the pili muscle to the base. A subpopulation of hair follicle keratinocytes has been identified in the upper follicle near the insertion site of the arrector pili.101,102 This area has been termed ‘the bulge’, and these cells may be involved not only in the regeneration of the anagen hair follicle, but also in the long-term maintenance of the epidermis.103 Within the specialized environment of the bulge are multipotent stem cells, Merkel cells, and melanocytes, which are thought to interact, leading to the differentiation of stem cells into the components of the hair follicle, sebaceous gland and epidermis.104107 The exact signaling and control of these stem cells is not known, but it appears that Lhx2 transcription factor plays an important role in their regulation in addition to adhesion molecules, epidermal growth factor, nerve growth factor, and platelet-derived growth factor.106,107 Lhx2 has been shown to have a role in regulation of these bulge region stem cells in embryonic and postnatal hair follicle growth and in wound healing.107109 The integrity of the hair shaft is related to its protein constituents, including the intermediate filament hair keratins and high-sulfur proteins, and to the strong disulfide bonding between these proteins.98 In neonates, hair may be a source of valuable clinical information: neonatal hair shaft analysis as a marker for intrauterine exposure to drugs of abuse having emerged as a useful tool over the last decade.103115