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Embryologic Development

All constituents of human skin are derived from either ectoderm or mesoderm. The epithelial structures, i.e., epidermis (surface and infundibular), apocrine units, sebaceous units, hair follicles, eccrine units, and nail units, come from ectoderm. Melanocytes, nerves, and specialized sensory receptors develop from neuroectoderm. The other elements in skin, i.e., Langerhans” cells, macrophages, mast cells, fibrocytes, blood vessels, lymph vessels, muscles, and adipocytes originate from mesoderm.

In a 3-week-old embryo, the primordial epidermis consists of a single layer of flattened epithelial cells (Fig. 1.3A). By 4 weeks (Fig. 1.3B), that epithelium has developed into a basal germinative layer made up of cuboidal cells and an outer layer of slightly flatter cells that possess microvilli and cytoplasmic blebs along a border that faces amniotic fluid. The outer layer of loosely interconnected cells, known as periderm, functions as a protective, yet permeable, barrier until epithelial cells of an evolving epidermis are able to cornify. Near the end of the first trimester (Fig. 1.3C), several layers of large cells rich in glycogen appear in the middle of a still-developing epidermis. Unlike cells of the periderm, those intermediate cells contain clumps of cytoplasmic tonofilaments that at intercellular junctions connect with specialized contacts called desmosomes. After the fifth month, keratohyaline granules appear in the upper part of the intermediate zone, basal germinative cells proliferate more rapidly, and epidermal cells near the surface lose their nuclei and show signs, progressively, of cornification, which is completed during the sixth month of gestation (or shortly thereafter, depending on the region of the body), at which time remnants of periderm are sloughed from the surface of the skin. By term, the cornified layer has come to function as a semipermeable barrier.

Figure 1.3

A-C. Histogenesis of epidermis from a single layer of undifferentiated epithelial cells to a multilayered cornifying epithelium.

The eyebrows of a 9-week-old embryo are the sites at which impending differentiation of hair follicles is noticeable first. Development of hair follicles begins on the head during the first trimester and proceeds caudally, not being detectable on the trunk until the fourth month. Clusters of mesenchymal cells congregate beneath discrete loci that resemble crescents made up of crowded germinative epithelial cells at the periphery of which the cells are columnar and arrayed in a palisade (Fig. 1.4). The cluster of mesenchymal cells is destined to become the future follicular papilla, and the aggregation of germinative cells arranged in the shape of a bow gives rise to the entire future infundibuloapocrine-sebaceous-follicular unit.1 The aggregation of germinative cells is known conventionally, and incorrectly, as a “hair germ,” a designation that does not give recognition to the difference between a hair (the cornified product of maturation of matrical cells situated in the center of a bulb of a follicle) and a follicle (the entire epithelial structure that produces and envelops a hair). Neither is the term “follicular germ” really accurate for designating the germinative cells of the infundibuloapocrine-sebaceous-follicular unit (although we employ that term in the interest of brevity). The germ consists of cells that not only will differentiate into a follicle, but into infundibulum and apocrine and sebaceous units, too. A second phalanx of follicular germs and the papilla associated with them emanates from surface ectoderm at sites nearly contiguous with the first generation. The duo, one, i.e., the germ, being larger than the other, i.e., the papilla, continues, for weeks, to come into existence episodically and asynchronously with one another, and to move through the future dermis. This dramatic series of changes culminates, by approximately the 28th week of gestation, in the formation of an entire infundibuloapocrine-sebaceous-follicular unit. The infundibulum, a funnel-shaped epithelial structure that is continuous above with surface epidermis and below with the isthmus of the hair follicle, actually is not part of the folliculosebaceous unit, but is epidermis, that particular epithelium being divisible morphologically in two parts continuous with each other, that is, surface and infundibular. The apocrine unit springs from the infundibulum.

1The conventional designation “folliculosebaceous-apocrine unit” is incorrect here because in an embryo, the apocrine unit derives from infundibular epidermis and the sebaceous unit from the junction of infundibular epidermis and follicle. That being so, the unit, in its entirety, is a tetrad, to wit, an infundibuloapocrine-sebaceous-follicular one.

 

Figure 1.4

A-D. Development of an infundibuloapocrine-sebaceous-follicular unit in an embryo consequent to the inducing effects of a follicular papilla of germinative cells housed in a crescentic mass at the base of the future surface epidermis. Germinative cells proliferate to become the infundibular epidermis, apocrine unit, sebaceous unit, and hair follicle. The bulge of the follicle situated beneath the future sebaceous gland represents the presumptive attachment site for muscles of hair erection. The future apocrine gland (not pictured) derives from the future infundibular epidermis.

Cells of a follicular germ divide rapidly and grow downward as a solid column of epithelium that penetrates the developing dermis and, on the scalp, reaches eventually far into the subcutaneous fat. The base of a column of follicular cells becomes bulbous as it appears to catch and partially enclose a spade-shaped unit of highly cellular mesenchyme that becomes a follicular papilla (a structure not to be confused with a dermal papilla, which is apple-shaped and, in sections of skin cut routinely, is seen to alternate with epidermal rete ridges).

Matrical cells, i.e., generative ones situated at the base of the bulb of a follicle, proliferate and mature into three distinct components of a future follicle; those in the center of the matrix eventuate in a filamentous fully cornified hair, those off-center come to form a tube of corneocytes known as inner sheath, and those at the periphery result in a more formidable enveloping viable epithelium referred to as outer sheath. An embryonal hair itself, consisting only of cortex and cuticle, is pushed upward by a stream of progressively cornifying cells that originate in the matrix. By the 17th week, the first fine wisps of hair emerge from ostia on the eyebrows and forehead and, by 18 weeks, delicate hairs cover the entire scalp. By 20 weeks, those lanugo hairs blanket the surface of the skin, except for palms, soles, dorsa of terminal phalanges of digits, glans penis, and labia minora.

As it descends into the dermis, a developing follicle is a column of epithelial cells. Near the 16th week, some of those cells crowd together at three distinct loci and expand as hemispheres into the mesenchyme. The lowest of the outgrowths, designated “the bulge” (a translation of der Wulst, the name given to it by German histologists of the 19th century), actually will become a series of bulges that emanate from the lower half of the isthmus and the upper part of the stem of the follicle, the series of bulges serving as sites of attachment for fascicles of smooth muscle of hair erection. Those muscles, which come into being late in the second trimester from elongated mesenchymal cells stationed in the dermis, extend obliquely upward from bulges to other sites of attachment, presumably, the base of epidermal rete ridges (Fig. 1.5).

Figure 1.5

In an embryo, a muscle of hair erection is seen to attach to a bulge of the follicle in the center of the photomicrograph. The other end of the muscle presumably connects to the base of epidermal rete ridges, although hardly ever is that seen in a section prepared conventionally, such as this one.

At this juncture it must be made crystal clear that “the bulge” proper refers only to the protrusion known as der Wulst, which, in time, becomes individual bulges that serve as the lower sites of attachment for fascicles of smooth muscles of hair erection. The cells of the middle protuberance, which is positioned at the junction of infundibular epidermis and follicular epithelium, become ever more laden with lipid and, in the process, come to form lobules of a sebaceous gland that is connected by a narrow cornifying duct to a canal in the center of the infundibulum. Maternal androgens especially, but also endogenous fetal hormones, influence the development of sebaceous glands before birth and in the weeks immediately following it. Commencing at about 15 weeks of gestational life, synthesis and secretion of products of sebocytes contribute to the lipid-rich vernix caseosa that coats a fetus during the third trimester.

Apocrine glands and ducts take origin, not from follicle itself, but from infundibular epidermis, and they do that in the form of an uppermost protuberance of epithelial cells, which descends as a cord through the reticular dermis and, by 24 weeks, becomes coiled at its base in the subcutaneous fat. The coiled portion becomes an apocrine gland and the straight part above it becomes an apocrine duct whose lumen enters the upper part of the future infundibulum, just above the entrance of a sebaceous duct and on the side opposite it, the sebaceous duct entering the base of the infundibulum at its junction with the isthmus. Canalization of cords of apocrine ductal cells proceeds as vacuoles form between cells in the center of the cylinders and, by virtue of that change, a lumen soon comes into being. The segment of apocrine duct that spirals through infundibular epidermis is analogous to that of the eccrine duct that spirals through surface epidermis; both are acrosyringia that cornify. Anlagen of apocrine glands are said to develop from all future infundibula, but after the fifth month of intrauterine life, most begin to regress so that by term they remain at only a few sites, namely, axillae, areolae, in periumbilical and anogenital skin, in external auditory canals where they are known as ceruminous glands, and in the eyelid where they are called Moll’s glands. Although, by 7 months apocrine glands are capable of secreting a milky fluid, they are dormant after birth and only begin to secrete again at puberty. Mammary glands also are apocrine glands, and they at puberty are capable of manufacturing, by virtue of the effects on them of prolactin, a milky secretion, colostrum, which is transported through lactiferous ducts to infundibula in the nipple, through which ostia it emerges on the surface of the skin. Parenthetically, the breast is not an organ per se, but a specialized region of skin and subcutaneous tissue.

In sum, the germ in an embryo that gives rise to an infundibuloapocrine-sebaceous follicular unit makes its appearance on the undersurface of developing epidermis, appearing there as a crescent of germinative cells situated just above a distinctive aggregation of mesenchymal cells, i.e., a follicular papilla. A protrusion of those germinative cells descends progressively into the dermis, preceded in its course by the follicular papilla to which it is wedded forever after, i.e., for a lifetime. Soon three bulges protrude from the epithelium of the descending column, they representing, in descending order, a future apocrine unit that derives from what will be infundibular epidermis, a future sebaceous unit from the junction of future infundibulum and future isthmus of a follicle, and future attachment sites of muscles of hair erection from the lower part of the isthmus and the uppermost part of the stem. At the base of a follicle, the papilla invaginates the bulb. Matrical cells in a bulb differentiate, from inside out, into hair, inner sheath, and outer sheath.

Eccrine units appear first on palms and soles of a 12-week-old embryo as a nubbin of germinative cells positioned at the base of epidermal rete ridges (Fig. 1.6). Those proliferations are independent entirely of infundibuloapocrine-sebaceous-follicular units, do not resemble follicular germs, and are unaffiliated with a papilla of mesenchymal cells. Whereas incipient follicles consist of germinative cells arranged in the shape of a crescent, incipient eccrine units are shaped like a nubbin. Rather thin columns of epithelial cells filled with glycogen move straight down into the dermis and upward through the epidermis. The outer layer of those columns is continuous with basal cells of the epidermis, whereas the core connects with cells in the intermediate zone of the evolving epidermis. The intraepidermal segment of eccrine ducts, termed acrosyringium and an equivalent of the intrainfundibular part of the apocrine duct, develops a lumen in the same manner as the apocrine duct, i.e., by confluence of cytoplasmic vacuoles in epithelial cells in the center of columns, that segment also cornifying in the same manner as does the acrosyringium of apocrine units. Just as an acrosyringium of an apocrine duct spirals through infundibular epidermis, so, too, does an acrosyringium of an eccrine duct spiral through surface epidermis. Subsequently, luminal (cuticular) cells of the acrosyringium, but not the more peripheral (poroid) cells, undergo cornification as evidenced by the appearance in some of them of keratohyaline granules and of cytoplasm that is eosinophilic. When downgrowth of columns reaches the deep part of the reticular dermis or subcutaneous fat, the lowest portion of them becomes coiled. Periluminal cells of eccrine glands develop either pale cytoplasm (pale cells) or dark cytoplasm (dark cells). By the sixth month of intrauterine life, when secretion of sweat begins, cells at the periphery of eccrine glands acquire properties of myoepithelium. From the base upward, a mature eccrine unit consists of a coiled secretory gland, a coiled intradermal duct, a straight intradermal duct, and a spiraled intraepidermal duct.

Figure 1.6

Development of an eccrine unit from undifferentiated epidermal cells at the base of a rete ridge. No structure comparable to a follicular papilla participates in formation of an eccrine unit.

Epithelium that will become a future nail unit at first is indistinguishable from epidermis adjacent to it. During the first trimester of embryogenesis, a smooth, shiny, quadrangular zone, demarcated proximally and laterally by a continuous shallow groove, can be recognized in the skin on the dorsal surface distally of each digit. The epithelium in that circumscribed locus is divided arbitrarily into three layers, to wit, surface, intermediate, and germinative. At nine weeks, a column of germinative cells, the anlage of nail matrix, grows proximally and slants downward obliquely for a short distance into the dermis (Fig. 1.7). Later, the far boundary of the matrix is delimited clinically by a lunula, a whitish zone in the shape of a hemiellipse that extends just beyond the proximal nail fold and is apparent most readily on thumbs. A proximal nail fold forms dorsally in the angle between matrical epithelium and epidermis. At 13 weeks, four components of the epithelium of a developing nail unit are visualizable histologically, namely, the basal, spinous, granular, and cornified layers. This region, now termed the epithelium of the nail bed, loses its granular zone by the 20th week. Earlier, at 14 weeks, the proximal part of a nail bed comes to be covered by a firm plate of cornified cells that derives from the matrix and matures into the nail itself, a structure that cornifies considerably before any other cutaneous epithelium. The cuticle refers to a soft cornified layer that extends from the ventral surface of the proximal nail fold onto the proximal part of dorsal surface of the nail plate. By 16 weeks, the nail plate has advanced to cover the proximal half of the nail bed and, by the 20th week, covers it completely, at which time the fetal nail unit resembles that of an adult.

Figure 1.7

Evolution of a nail unit in an embryo. Nail plate, hair shaft, and epidermal cornified layer (stratum corneum) represent products of maturation of generative cells of the nail unit, the hair follicle, and the epidermis, respectively.

Two types of nonkeratocytic cells, i.e., melanocytes and Langerhans” cells, migrate during embryogenesis to the epidermis and epithelial structures of adnexa. By the eighth week, primordial melanocytes from the neural crest arrive at the basal layer. Subsequently, they acquire dendrites and, by about the fourth month, begin to synthesize melanosomes and to transfer them to keratocytes. Functioning melanocytes are noticeable among follicular matrical cells by the fourth or fifth month of gestation, i.e., after the time they arrive in the epidermis.

Langerhans” cells have been identified in the intermediate zone of the epidermis of embryos as early as the sixth week of development, having originated as hematopoietic stem cells of the yolk sac and/or the liver, the two major organs of hematopoiesis in an embryo. At this stage, they are less dendritic and show phenotypic markers different from those in late fetal or postnatal skin. Phenotypically mature Langerhans” cells are appreciable in epidermis at about 12 weeks, they having derived from mesenchymal precursors in the bone marrow. Whether the presence of Langerhans” cells in the epidermis results from continuous migration of those cells from bone marrow to skin or from replication of ones already at home in the epidermis is not known.

Merkel cells are thought to issue from primitive ectodermal cells, i.e., germinative cells, within embryonic epidermis. In plantar skin, Merkel cells have been identified as early as the 12th week of gestation. In the 16th week, Merkel cells make their appearance first in surface epithelium of the fingertips and nail beds, and then elsewhere on what is called glabrous skin, glabrous referring to skin that is smooth and which sports vellus hairs, but not terminal ones.

Early in embryogenesis, the interface between epidermis and dermis is flat. During the first trimester, a basement membrane, synthesized mostly by epidermal basal cells, forms at the junction of dermis and epidermis. Around the second trimester, the interface between dermis and epidermis develops into a highly complex, multilayered structure that, as visualized through an electron microscope, consists of a lamina lucida and a lamina densa, and contains molecules common to all basement membranes. At about 12 weeks, the dermoepidermal interface is punctuated at intervals nearly equidistant from one another by proliferations of germinative cells. These clusters represent anlagen of infundibuloapocrine-sebaceous-follicular units and of eccrine units, the former being crescentic and the latter being nubbin-like. Starting in the sixth month of fetal life, nipple-shaped insertions of connective tissue, i.e., dermal papillae, fit into hollows on the undersurface of the epidermis. The follicle, but not the epidermis, epithelium of the nail unit, or epithelium of eccrine glands, is typified at its base by a discrete aggregation of mesenchymal cells, the follicular papilla, which is enclosed nearly completely by matrical cells of the follicular bulb; at its base, the papilla is continuous with perifollicular fibrous sheath. A unit of follicular papilla and matrix is analogous, conceptually, to a unit formed by papillary dermis and epidermal basal cells, and to a unit constituted of nail matrix and connective tissue adjacent to it.

Embryonal dermis consists at first of numerous, crowded, stellate mesenchymal cells suspended in abundant acid mucopolysaccharides. By the 12th week of life, fibrocytes produce delicate collagen bundles and, by the 16th week, more mature bundles of collagen. The papillary and reticular compartments of the dermis become recognizable as distinct entities by about the fourth month of intrauterine life. Bundles of collagen in the papillary dermis are much thinner than those in the reticular dermis. As fibrillar elements of the fetal dermis increase steadily and cellular components decline pari passu, the dermis acquires features typical of fully formed connective tissue. By 24 weeks, elastic fibers, made also by fibrocytes, first become visible among collagen bundles in the dermis.

Dermal dendrocytes, a heterogeneous population, are indistinguishable by conventional microscopy from fibrocytes and, like fibrocytes, are scattered throughout the dermis. The exact nosologic status of these cells, characterized by stellate shape and reactivity to Factor XIIIa, is not known, but they differ from fibrocytes by displaying markers indicative of macrophagic nature. They are thought to be derived from bone marrow, but whether or not they represent effete Langerhans” cells devoid of Birbeck granules has yet to be determined.

Late in the first trimester, dermal networks of blood and lymph vessels originate from mesenchymal cells, but arterial and venous plexuses, one set in the upper part of the reticular dermis and the other in the lower part of it, are not obvious until the third trimester. Mast cells make their appearance in the dermis during the second trimester, a time when macrophages from the bone marrow arrive there. Mast cells, like Langerhans” cells, derive from stem cells located in the bone marrow. Late in the second trimester, beneath the dermis, lobules of mesenchymal cells that surround newly formed blood vessels begin to differentiate into primitive adipocytes that become filled steadily with lipids; the subcutaneous fat thus comes into being.

Cutaneous nerves take origin from ectoderm of the neural crest and, by the fifth week, are detectable in embryonal dermis. In succeeding weeks, an elaborate neural network is fashioned of autonomic motor nerves that innervate blood vessels, muscles of hair erection, eccrine and apocrine glands, somatic sensory nerves, and specialized sensory end organs, e.g., Pacini’s corpuscles, Meissner’s corpuscles, and Krause’s mucocutaneous end organs.

Stratification of epidermal cells depends, in large part, on an intact basement membrane. That dependence is apparent during re-epithelialization of healing wounds. Epithelial cells of infundibular epidermis and of eccrine ducts, and much less so from nearby surface epidermis, migrate and, at first, cover denuded dermis with a single row of cells. Once the defect is covered, basal cells generate epidermis anew. The reconstitution of surface epidermis from keratocytes of infundibular epidermis and of eccrine ducts demonstrates graphically the capability for regeneration of different kinds of epithelial cells. The interdependence of epithelium and mesenchyme is exemplified by the situation of the infundibuloapocrine-sebaceous-follicular unit during embryogenesis; that distinctive epithelial structure does not emanate from surface ectoderm in the absence of an inducing mesenchymal papilla, and, conversely, a follicular papilla will not become manifest in the absence of a covering epithelium. The influence, reciprocally, of cutaneous epithelium on contiguous cutaneous connective tissue and of contiguous connective tissue on epithelium persists throughout life.

In conclusion, development and maintenance of the skin depend on interactions between epithelium and mesenchyme, between germinative epithelial cells and components of their basal lamina, and of epithelial cells with one another. These interactions, collectively, result in formation of a heterogeneous but unified structure, i.e., skin, which exhibits marked regional differences in form, color, and consistency.