Skin Development and Maintenance 2  CHAPTER


Skin Development and Maintenance
Maranke I Koster, Cynthia A Loomis, Tamara Koss and David Chu

An overview of key events in the development of skin and its special-
Chapter Contents ized structures is shown in Figure 2.1.
Embryonic origin of the skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Epidermal development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Development of specialized cells within the epidermis . . . . . . . . . . . 57
The ectoderm that covers the developing embryo after gastrulation is
Development of the dermis and subcutis . . . . . . . . . . . . . . . . . . . . . . . . 58
a single-layered epithelium (Fig. 2.2A). The first step in epidermal
Development of the dermal–epidermal junction . . . . . . . . . . . . . . . . . 59 development occurs when cells of the surface ectoderm adopt an epi-
Development of skin appendages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 dermal fate1. Although this process does not result in major morpho-
logic changes, it is marked by dramatic alterations in gene expression
Skin stem cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
that result in the formation of the embryonic epidermis, which initially
Prenatal diagnosis of genodermatoses . . . . . . . . . . . . . . . . . . . . . . . . . . 63 consists of only a basal layer (Fig. 2.2B). Basal keratinocytes subse-
Significance of skin development in postnatal life . . . . . . . . . . . . . . . 63 quently generate cells of the periderm, a single cell layer that covers the
developing epidermis until the cornified cell layer is formed (Figs
2.2C–F & 2.3A,B). Although the precise function of the periderm is not
known, it is believed to participate in the exchange of substances across
INTRODUCTION fetal skin and protects the developing epidermis from the amniotic
Development of the human embryo is a complex process involving The embryonic epidermis begins to stratify at approximately 8 weeks’
highly orchestrated cell movements, proliferation, death and differen- estimated gestational age (EGA)2. At this time, basic organogenesis is
tiation. This chapter focuses on key events and regulatory mechanisms complete and bone marrow hematopoiesis commences, marking the
that result in skin morphogenesis, maintenance and regeneration. The transition from embryo to fetus. During the first stage of epidermal
spectrum of cutaneous abnormalities that can result from mutations stratification, an intermediate cell layer is formed between the basal
in genes with critical roles in skin development is discussed. Ulti- layer and periderm (Figs 2.2D & 2.3B). Unlike suprabasal keratinocytes
mately, improved understanding of the pathways and signaling cascades in the postnatal epidermis, the intermediate layer consists of actively
that are disrupted in genetic skin disorders will aid in the development proliferating cells. As a consequence, it is able to expand to accom-
of therapeutic approaches for patients with acquired as well as inherited modate the rapid growth of the embryo as well as create additional
skin disorders. layers of intermediate cells over the next several weeks (Fig. 2.2E).
However, the intermediate cell layer only exists temporarily during
epidermal development, as it is eventually replaced by layers of post-
EMBRYONIC ORIGIN OF THE SKIN mitotic keratinocytes undergoing terminal differentiation.
The skin is composed of diverse cell types of both ectodermal (e.g. Terminal differentiation, the process resulting in the formation of
keratinocytes, melanocytes, Merkel cells, neurons) and mesodermal mature keratinizing epidermal cells, begins during the second trimes-
(e.g. fibroblasts, hematopoietic cells such as Langerhans cells, endothe- ter. Early cornification can be observed within the hair canal at
lial cells) lineages. To understand the origins of these cells, it is impor- approximately 15 weeks’ EGA2a, but it does not commence in the
tant to review the early stages of embryogenesis. Immediately after interfollicular epidermis until 22–24 weeks’ EGA, occurring first in
fertilization, cells divide rapidly, and by the end of the first week, the the skin on the head, palms and soles. Expression of the p63 gene is
embryo begins to implant into the uterine wall. During the third week, required for the process of epidermal stratification. The process begins
the embryo undergoes gastrulation, a complex process resulting in the when cells in the intermediate layer permanently withdraw from the
formation of the three embryonic germ layers: endoderm, mesoderm cell cycle and differentiate into spinous and granular cells (Fig. 2.2F).
and ectoderm. The cornified cell layer, which is composed of “dead” keratinocytes
During the next stage of embryogenesis, ectodermal cells commit to (corneocytes) held together by a matrix of proteins and lipids (see Ch.
either a surface ectodermal or neuroectodermal fate. The surface ecto- 56), subsequently starts to form and is several cells thick by 24–26
dermal cells eventually differentiate into the keratinocytes of the weeks’ EGA. The corneocytes are a reflection of the closely regulated
embryonic epidermis, whereas the neuroectodermal cells invaginate to process of terminal differentiation that is required for normal func-
create the neural tube in a process called neurulation. As the neural tioning of the skin. At the same time, the periderm detaches from the
tube forms, cells in its dorsal portion separate to form the neural crest. underlying epidermis and is sloughed off into the amniotic fluid, with
An important neural crest-derived cell in the skin is the melanocyte. remnants contributing to the vernix caseosa that coats newborns.
Although Merkel cells were once believed to be neural crest derivatives, During the third trimester, the number of keratohyalin and lamellar
it was recently established that they descend from the epidermal granules as well as stratum corneum layers increase. By the mid third
lineage. The lineage of the dermis depends on its location. Whereas the trimester, the epidermis is morphologically similar to adult skin (Figs
dermis (and other mesenchymal structures) of the face and frontal scalp 2.2G & 2.3C), although it does not acquire full barrier function until
are derived from the neural crest, the dermis elsewhere is derived from a few weeks after birth.
the mesoderm. Knowing from which germ layer and lineage different
cell types in the skin derive helps one to understand the pathophysiol- Clinical Relevance
ogy of cutaneous disorders ranging from congenital melanocytic nevi Genetic abnormalities affecting various stages of epidermal morpho-
(where “neurotization” is explained by the derivation of both melano- genesis have been found to underlie inherited skin disorders in
cytes and peripheral nerve sheath cells from the neural crest) to humans. However, generalized abnormalities in epidermal specifica-
Waardenburg syndrome (where craniofacial dysmorphism and hearing tion, the process through which the surface ectoderm adopts an epi-
impairment as well as pigmentary abnormalities reflect disrupted dermal fate, have not been identified, and it is likely that such defects 55
migration and survival of neural crest-derived cells). would be incompatible with survival past the first trimester. Mosaic

resulting in the formation of the basal layer of the epidermis. Fig. 2.  D Epidermal stratification begins with the formation of a highly proliferative intermediate layer between the basal layer and the periderm.2  Development of the epidermis. 2.   a single-layered epithelium that initially covers the developing embryo. B Through changes in gene A B expression. F Intermediate cells ultimately withdraw from the cell cycle and differentiate into spinous and granular keratinocytes. cells of the surface ectoderm adopt an epidermal fate. A The DEVELOPMENT OF THE EPIDERMIS epidermis develops from the surface ectoderm. The timeline indicates the time of initiation defined by estimated gestational age (EGA) and duration of pregnancy (by Clinical timing Fetal age Epidermal Dermal-subcutis Appendage last menstrual period [LMP]). Refers to skin on the SECTION of pregnancy development development development 1 LMP (weeks) EGA (weeks) back unless otherwise noted.1  Critical events in the development of the CRITICAL EVENTS IN THE DEVELOPMENT OF SKIN AND ITS SPECIALIZED STRUCTURES skin and its specialized structures. a cell layer that covers the C D developing epidermis until cornification occurs. Overview of Basic Science 6 4 Periderm Basal layer Tooth primordia Periderm Nail primordia 10 8 Intermediate layer Volar eccrine gland Dermal-subcutaneous Basal layer boundary distinct primordia Melanocytes Hair follicle/sebaceous Langerhans cells gland primordia 14 12 Merkel cells Papillary and 18 16 reticular dermal boundary distinct Second trimester 22 20 Dermal ridges Trunk eccrine gland primordia Periderm sloughs 26 24 Stratum corneum Granular layer Spinous layer 30 28 Basal layer 34 32 38 36 42 40 Birth 3 weeks' postnatal age Fig. G Surface ectoderm Spinous layer Basal layer Granular layer Periderm Cornified layer Intermediate layer 56 . G The periderm is replaced by E F the cornified cell layer. C Basal cells subsequently give rise to the periderm. E The intermediate layer becomes several cells thick over the next few weeks.

armor-like shell keratinocytes is not seen until 5 months’ EGA. Melanocyte precursors migrate away from the shiny. and it increases further (~3000 cells/mm2) as the epidermis (ABCA12) (see Ch. which are thought to barrier function until 3 weeks of age.g. Cutaneous melano- spectrum3. However. Photomicrographs courtesy of Dr Karen Holbrook. from Loomis CA. which originate from the neural crest via the distinct LI and the erythroderma with fine white scales of CIE. All of these outcomes can result Melanocytes can be first identified within the embryo’s epidermis at from mutations in the same set of genes that encode proteins essential approximately 50 days’ EGA. Two populations of specialized cells – melanocytes and Langerhans cells There are a number of genetic disorders that result in abnormal – migrate to the epidermis during early embryonic development. Philadelphia: WB Saunders. Even healthy full-term infants do not attain full skin tribution pattern that follows Blaschko’s lines. Fig. later More deleterious mutations in the ABCA12 gene represent the cause in gestation. depends on environmental conditions. The immaturity of the stratum corneum results migrate to the epidermis or undergo apoptosis. Chu D. an especially severe and often fatal disorder adults (800–1500 cells/mm2). stratifies (80–90 days’ EGA) and the appendages begin to develop. newborn skin is not fully ment of the nose and ears. plate-like brown scales of in the skin. but also com. and excessive absorption of topical medications keratinocytes or melanocytes) and/or its appendages often have a dis. the embryonic epidermis consists of two layers – a superficial periderm layer CHAPTER A overlying a basal layer. including transglutaminase-1 HMB45 monoclonal antibody and their dendritic morphology. TGM1). However. most of these dermal melanocytes before 28 weeks’ EGA. transparent membrane that is formed by aberrant stratum neural tube within the mesenchyme beneath the primitive epidermis. based on their positive reactivity with the for formation of the epidermal barrier. Epider- (an enzyme that cross-links lipids to the cornified cell envelope. two forms of autosomal recessive ichthyosis that exist on a scalp and face. but also in premature infants. The structural features of prema- represent the migration pathways of epidermal cells during embryonic ture skin and adult skin are summarized in Table 2. but they are not fully functional until the second trimester. epidermal melanin production of cornification characterized by aberrant epidermal maturation. In: Eichenfield LF. the phenotypes that can develop following a collo­ cytes can also arise from Schwann cell precursors located along nerves dion membrane include not only the large. B By 72 days. keratin 1 or keratin 10) and DEVELOPMENT OF SPECIALIZED CELLS sebaceous nevi (where the underlying genetic defect remains unknown WITHIN THE EPIDERMIS but is thought to be lethal if present in all the cells of the body) (see Ch. mal melanocyte density is high early in embryonic development (1000 lipid processing enzymes (ALOXE3. infants. C D skin conditions that result in abnormalities of the epidermis (e. most of these infants manifest They follow a characteristic trajectory. One clinical presenta. Frieden IJ. After shedding the membrane. dorsal neural tube. development. Fetal skin development. Eventually.1. severe ectropion and eclabium. The extreme phenotype of HI highlights the pigmented and subsequently darkens over the first few months importance of lipid transport into lamellar bodies for epidermal forma.3  Development of the skin. Melanocytes are derived from the neural crest that forms along the tion of such conditions is a “collodion baby” born encased in a taut. Textbook of Neonatal Dermatology. and melanosome transfer to Patients with HI are born with a tremendously thick. By the time of birth. epidermal differentiation and barrier formation. Esterly NB (eds). the density decreases and becomes similar to that of young of harlequin ichthyosis (HI). Even though all melano- of hyperkeratosis. Classic examples include epidermal nevi (with underly- ing defects including mosaicism for mutations in genes encoding the fibroblast growth factor receptor 3. cytes are functional and in place at birth. D An early peg-stage follicle from a mid second trimester fetus. The more superficial bulge consists of the developing sebaceous gland (arrowhead). 2. pletely normal appearing skin. and distally along the extremities. ventral pathway5. especially those born embryonic development. does not begin until 3–4 months’ EGA. A At 36 days’ estimated gestational age. 62). Koss T. the basal layer has given rise to the highly proliferative 2  Skin Development and Maintenance intermediate cell layer. 2007:1–17. Abnormalities in the stratum corneum are present not only in infants Active melanocytes are also present throughout the dermis during with ichthyosis. of life. whereas the deeper bulge represents the B insertion point of the future arrector pili muscle and the location of the presumptive follicular stem cells (arrow). corneum. which leads to an increased risk of dermal melanocytes have disappeared. 57). 2nd edn. this process is most pronounced in more darkly pigmented tion and function. Referred to as a “self-healing” collodion Melanocytes are present in the epidermis by the middle of the first baby. and underdevelop. ALOX12B) and lipid transporters cells/mm2). anteriorly over the (CIE). of infection. moving dorsolaterally and then with lamellar ichthyosis (LI) or congenital ichthyosiform erythroderma ventrally around the trunk to the ventral midline. the latter is an example of a dynamic epidermal phenotype that trimester. 57 in impaired barrier function. with the exception of certain . dehydration. or chemicals4. C A distinct granular cell layer and stratum corneum are seen in neonatal skin.

III and IV) and some microfibrillar components. Structural features and antigens Well-developed adhesive structures. Several inherited pigmentary disorders result from genetic defects that Although embryonic dermal cells are capable of synthesizing collagens lead to abnormal migration and proliferation of neural crest-derived (e. these melanocyte precursors (melanoblasts). there is no distinct demarcation between the cells that will give rise to Clinical Relevance the dermis and those that will give rise to musculoskeletal components. the reverse of what is seen in the forehead. and adult skin. the dermal mesenchyme of the back originates and nerve fibers. newborn. and slightly later in interfollicular of the face and anterior scalp (as well as the underlying muscle and skin. and the dermal opmental origin of Merkel cells has been the subject of longstanding mesenchyme of the extremities and ventral trunk is thought to arise controversy. highly innervated neuroendocrine cells involved in that is incompletely understood. Large in reticular dermis.g. cytokeratin 20 and neuropeptides. from the dermomyotome of the embryonic somite. are initially identified within the epidermis during derived exclusively from the ectoderm. but recent studies have demonstrated that mammalian from the lateral plate mesoderm. KIT receptor)8 (see Ch. PAX3.2 mm 2. By 12–15 A number of different causative genes leading to this phenotype weeks’ EGA. dorsal aspects of the distal extremities have been identified.g. thereby explaining the core granules. a distribution pattern adult dermis. However. the ratio syndrome are characterized by achromic patches of skin on the central of collagen III to collagen I is 3 : 1. COMPARATIVE FEATURES OF PREMATURE. presumptive dermal fibroblasts are situated lineage7. for dermal melanocytoses and blue nevi (see Ch. which first occurs at 13 weeks’ EGA. under the developing epidermis9. body area Dermal–epidermal All known adult antigens expressed. As noted above. These cells are detected as early as 8–12 weeks’ EGA depending on the body site. These cells can be distinguished by their characteristic dendritic in the developing neural crest. form network Hypodermis Well-developed fatty layer Well-developed fatty layer Well-developed fatty layer Table 2. Of note. explaining the Hirschsprung disease (as morphology. densations becomes distinct at approximately 9 weeks’ EGA. London: Mosby. large junction fewer and smaller desmosomes similar to those of the adult number of antigens expressed Papillary dermis • Boundary with reticular Present but not marked Present but not marked Marked dermis • Size of collagen fiber Small Small Small bundles • Cellular density Abundant Abundant Moderately abundant Reticular dermis • Boundary with the Marked Marked Marked subcutis • Size of collagen fiber Small Small to intermediate Large bundles • Cellular density Abundant Moderately abundant Sparse Elastic fibers Sparse. the basal layer of the epidermis. central abdomen and extremities. endothelin B receptor.1  Comparative features of premature. Pediatric Dermatology. AND ADULT SKIN Premature Newborn Adult SECTION Skin thickness 0. progressive changes in matrix organization and cell . which correspond to the most common locations (e. and are particularly dense on volar skin. The first trimester and are first detectable in this site as early as 40 days’ endothelin B receptor is found on melanoblast–ganglion cell precursors EGA. proliferate The demarcation between the dermis and underlying skeletal con- 58 or travel to the distal points of their embryonic migration pathway. Reproduced with permission from Schachner LA. The density of Langerhans cells in fetal skin remains low early in gestation and increases to typical adult levels during the third DEVELOPMENT OF THE DERMIS AND SUBCUTIS trimester. and the production of Birbeck granules6. microphthalmia-associated transcription factor [MITF]. Unlike the epidermis. anatomic sites (head and neck. They are found in facial dysmorphia in the neurocristopathy Waardenburg syndrome. receptor or its ligand. tiny with immature Small size and immature structure. and high levels well as pigmentary abnormalities) that is associated with defects in this of ATPase activity. Piebaldism and Waardenburg proteins are not yet assembled into complex fibers. HLA-DR and CD1c.g. 2010. Langerhans cell precursors appear within the epidermis during the endothelin-3. low melanin production dependent on skin type. small and immature in structure distribution similar to adult papillary dermis. that reflects the failure of melanocyte precursors to survive. the origin of the dermis varies the first trimester. expression of CD45. 66). SOX10. NEWBORN. which is mechanoreception. The devel. including those encoding transcription factors and presacral area). SNAI2) as well as membrane receptors and their ligands (e. The specification of dermal mesenchymal cells is a complex process Merkel cells. the dermal mesenchyme in palmoplantar epidermis. Langerin expression precedes CD1a acquisition. few mature Similar number of cells to young Numbers decrease with age. 4th edn. Merkel cells are derived from an epidermal rather than neural crest By 6–8 weeks’ EGA. Merkel cells are identified by the presence of cytoplasmic dense bone) is derived from neural crest ectoderm. melanin production melanosomes adult.1 mm 1 Epidermal surface Vernix (gelatinous) Vernix Dry Epidermal thickness ~20–25 microns ~40–50 microns ~50 microns Overview of Basic Science Stratum corneum 4–5 microns 9–10 microns 9–15 microns thickness 5–6 cell layers >15 cell layers >15 cell layers Spinous cell glycogen Abundant Little or none Little or none content Melanocytes High number of cells. 112). types I. are often associated with appendages On the other hand.9 mm 1. at this developmental stage. Hansen RC (eds).

point of the future arrector pili muscle and the location of the presump- tions in PORCN.3)14.g. The DEJ becomes progressively more complex. (see Ch. SHH also appears to be critical in mediat- anchoring filaments and anchoring fibrils are synthesized by basal ing the transition from telogen to anagen during postnatal hair cycling.2). The laxa associated with severe pulmonary. 28). apocrine and sebaceous including the vascular endothelial growth factor (VEGF) family as well glands) have both epidermal and dermal components that are critical as the tyrosine kinase receptors Tie-1 and Tie-2 and their stimulatory in embryogenesis. By 12 weeks’ EGA. the dermis is still thinner and more cellular depth of bulla formation. laminin. and in a mouse forming seven concentric cell layers (from outer to inner): outer root model. For example. As development progresses. Epidermolysis bullosa (EB) is a heterogeneous group of genetic disorders characterized by blister formation due to mechanical fragility of the 2  cellular dermis of the embryo is modified to the more rigid. At this stage. 68. The superficial portion of the developing hair follicle has two order characterized by areas of dermal hypoplasia (with fat herniation/ distinct bulges. the eyebrows. The basic pattern of the dermal vasculature is discernible by the end of the first trimester.g. The more superficial bulge consists of the developing hamartomas) in a distribution following Blaschko’s lines. gastrointestinal and genitourin­ epidermal placodes instruct the underlying dermal cells to condense ary malformations. the watery. acterize the adult DEJ. skin. and hairs are visible shortly thereafter. directs the keratinocytes of the placode to proliferate and extend deeper leads to aberrant TGF-β activity and defective elastic fiber assembly in into the dermis. The hairs continue to grow until 24–28 weeks’ EGA. Follicle formation is initiated by in regulatory proteins important for extracellular matrix development signals from the dermis that direct the embryonic epidermis to form can lead to abnormalities in the skin and other organs.g. a signaling mole- transition at 8 weeks’ EGA. critical for normal dermal development10. Most The embryonic DEJ consists of a lamina densa and a lamina lucida. proteoglycan-rich. tissues). leading multilayered structure in the second-trimester fetus. wound repair. heparan sulfate. growth factor (FGF) families of signaling molecules are also important 59 goid antigens are also expressed. with the type VII collagen-containing anchoring fibrils Members of the Wnt.morphology distinguish the fine weave of the papillary dermis located embryonic DEJ acquires the rete ridges and dermal papillae that char- directly beneath the epidermis from the thicker. almost all of the structures charac. 68. tightly regulated interactions between the early dermis and epidermis Nerve networks are formed by the mid to late first trimester. but the hair cycles for individual hair follicles become asyn- simple. bone morphogenetic protein (BMP) and fibroblast localizing to the sub-lamina densa. new hairs grow and push out the first The dermal–epidermal junction (DEJ) mediates adhesion between the group of telogen hairs. skeletal sebaceous gland. pro. is required for the stratification. deeper reticular dermis. coincident with the onset of epidermal cule secreted by cells of the developing hair follicle. Numerous DEVELOPMENT OF SKIN APPENDAGES molecular controls are involved in the regulation of angiogenesis. Sonic hedgehog (SHH). when distinct lobules separated by fibrous septae are in the structure and function of the various types of cutaneous append- formed. focal thickenings. EB can result from mutations in genes that encode several Skin Development and Maintenance acellular dermis characteristic of adult skin. and it is composed of molecules that are common to all basement leading to vellus and then adult-like terminal hairs on the scalp and in membrane zones (e. Placodes are mutations in the latent transforming growth factor-β (TGF-β) binding first seen on the scalp and face between 10 and 11 weeks’ EGA. they protein-4 gene (LTBP4) were recently found to underlie a form of cutis subsequently develop in a caudal and then in a ventral direction. the flat in hair follicle development and cycling. and then the hair shaft cuticle. called placodes (see Figs 68. The absence of LTBP4. 32). Goltz syndrome is caused by muta. Transcription factors with roles . catagen and telogen continues through- shearing forces on the skin (see Ch. an X-linked dominant dis. Electron micro- scopy can first detect definitive elastic fibers at approximately 22–24 weeks’ EGA. the developmental processes that regulate their formation are remarkably similar13. This pattern. 102). 68). and (e. nails. cortex and medulla (see dermis. collagens. the base of the developing hair follicle surrounds Another disorder characterized by abnormal dermal development is the presumptive dermal papilla. basal keratinocytes and the dermis and provides resistance against Hair cycling through anagen. the collagen proteins produced by the fibroblasts start to assemble into collagen fibers. type IV collagen. placode to the peg hair stage. Despite the differences third trimester. signaling molecules that are sent back and forth between these they tend to follow the vascular pattern. to the shedding of the second wave of fine lanugo hair follicles. and eccrine. thereby forming the hair germ (see Figs 68. and skin.2 & 68. The hair canal is fully formed by 18–21 weeks’ EGA. to represent pathways of epidermal development. Many genes important for hair follicle development and cycling have specific components of the DEJ start to appear after the embryonic–fetal been identified (see Ch.3). laminin 5 and the bullous pemphi.2 & 68. Skin appendages (hair. fibrous. when they leave the active growing phase (anagen) DEVELOPMENT OF THE DERMAL– and enter the short-lasting degenerative phase (catagen) and subse- EPIDERMAL JUNCTION quently the resting phase (telogen).2 & Goltz syndrome (focal dermal hypoplasia). The specific protein affected (and trimester. 28). Normal development of skin appendages depends on (Ang-1) and inhibitory (Ang-2) angiopoietin ligands (see Ch. The DEJ develops from a out life. chronous after birth. At birth. hairs become thicker and coarser with subsequent growth cycles. redundant skin). The follicles then start the second hair cycle by re-entering anagen. an extracellular matrix and form the presumptive dermal papilla. which continue to accumulate in the Clinical Relevance CHAPTER reticular dermis during the second and third trimesters. maturation of the dermal papilla and for the progression of the follicle teristic of the mature DEJ are in place (see Ch. generic basement membrane in the embryo to a highly complex. teoglycans)11. Hemidesmosomes. The third hair cycle is initiated perinatally. By the end of the second different components of the DEJ12. Clinical Relevance Mutations in the genes that encode a variety of dermal structural pro- teins (e. the dermis shifts from a non-scarring to a scarring form of the degree to which it is altered) largely determines disease severity. As development progresses. keratinocytes. many types of tissues. Genetic defects the formation of the hair follicle. Accumulation of subcutane. components of elastic fibers) and the enzymes that Hair Follicle Development process them underlie multiple forms of Ehlers–Danlos syndrome The complex dermal–epidermal interactions and genetic control mech- (characterized by skin hyperextensibility and fragility with poor wound anisms that occur in appendage development are best understood in healing) and cutis laxa (featuring lax. which are shed into the amniotic fluid. whereas the deeper bulge represents the insertion defects and mucosal papillomas. PORCN expression and resultant Wnt signaling originating sheath. Blaschko’s lines are thought Hair follicles undergo further maturation during the second trimester. undergoes extensive remodeling in utero and is not fully mature until after birth. and a failure in either component (or in communication ous fat begins during the second trimester and continues through the between them) leads to aberrant development. Fig. and involvement of extracutaneous tissues than the adult dermis. an effector of the Wnt signaling pathway that is tive follicular stem cells. inner root sheath. By 12–14 weeks’ EGA. ages. however.3). forming the hair peg (see Figs 68. The dermal papilla then protein that binds to fibrillin and controls the bioavailability of TGF-β. composed of Henley’s and Huxley’s layers from the ectoderm have been shown to regulate development of the and a cuticle.

including the ankyloblepharon–ectodermal keratinization begins distally and then continues over the nail bed dysplasia–cleft lip/palate (AEC) and ectrodactyly–ectodermal dysplasia– toward the proximal nail fold. which can be medulloblastomas. glandular structures form at the terminal portion for maintaining and repairing the tissue they reside in. and sweat cells in human palmoplantar skin is less clear. abnormal appendages result from disruption of cross-talk tive nail matrix cells. do not function in utero but mature and begin functioning of basal keratinocytes. Within the skin. Sweat gland development starts with the formation of large mes.17. sebaceous glands) can also be dence that they are found at the base of the rete ridges. preliminary nail is shed easily cleft lip/palate (EEC) syndromes (see Ch. originate independently. Unlike most other cinomas to arise (see Ch. this occurs via a loss of the desmosomal adhesions infrequently during periods of homeostasis. XLHED is a prime target of life. appendages. with the latter feature along the innermost ectodermal surfaces. By Stem cells are present in each self-renewing tissue and are responsible 16 weeks’ EGA. apocrine glands do not begin to form until the fifth month of gestation. which reside in the and subsequently become quiescent in the neonate. PTCH tumor suppressor gene that result in overactivation of the sonic enchymal bulges or pads (analogous to the paw pads of other mammals) hedgehog (SHH) signaling pathway. The flat. Eccrine glands. individual eccrine gland SKIN STEM CELLS primordia bud along the ectodermal ridges at regularly spaced intervals. The first. TA cells divide Unlike volar eccrine sweat glands. The buds elongate as cords of cells that enter the pad mesenchyme. However. can cause several types dorsal digit is the first skin structure to keratinize. believed to protect them from acquiring mutations during cell cycle nance of the adhesion between duct cells and the gland walls. carcinoma syndrome (Gorlin syndrome) is caused by mutations in the ter. TA cells withdraw from the cell postnatally. In these field. studies in mice and dogs have dem- onstrated an almost complete correction of the XLHED phenotype Nail Development upon prenatal or neonatal treatment with recombinant EDA protein16. where they give rise to epi- Ectodermal dysplasias are a large. which will later produce the differentiated nail between the developing epidermis and dermis. 108). 2. The nail bed on the that is required for epidermal morphogenesis. other ectodermal structures (e. which leads to sebaceous gland hypertrophy and increased synthesis and secretion of “full-blown” disease in affected males and areas of involved skin fol- sebum during the second and third trimesters. forming the proximal nail fold by 13 weeks’ EGA. and by 7 months’ EGA the clear cells and Epidermal Stem Cells mucin-secreting dark cells characteristic of apocrine glands can be visu. other . daughter transit amplifying (TA) cell. HED Sebaceous gland development parallels follicular development. Interfollicular eccrine glands. progression. epidermal stem Clinical Relevance cells are scattered within the basal layer. rologic and anterior–posterior axis development as well as hair follicle mal ridges are induced in the epidermis overlying these pads between formation20. of the buds and secretory and myoepithelial cells are visible. rectangular surface infants with XLHED are planned. This explains the broad range of developmental anomalies. The properties of stem cells. including HOXC13 relatively common type of ectodermal dysplasia that affects the sweat and FOXN1. hair follicle and tooth morphogenesis.2. nails. Mutations in EDA are Overview of Basic Science the upper portion of the hair canal.g. ectodermal dysplasias can also be caused by mutations obliquely into the mesenchyme along the proximal end of the early nail in genes that are required for epidermal development18. apocrine glands typically arise from the upper licles have been most extensively studied. interfollicular eccrine glands and frequently and ultimately differentiate into lineage-specific cell types. generating one new stem cell and one weeks’ EGA. and melanocytes are each maintained by different tion of the dermal component of the eccrine duct is also complete by stem cell compartments. Hypohidrotic ectodermal dysplasia (HED) is a are physically protected from environmental stress. In non-acral human skin. stem cells that maintain the epidermis and hair fol- Like sebaceous glands. Parallel ectoder. a gene plate. in follicular differentiation have also been identified.4)23. The presump. hair (hypotrichosis) and teeth (hypodontia). and the propensity for result in characteristic dermatoglyphics (fingerprints). basal layer together with TA cells22. which involutes over the first year during the initiation of appendage formation. at around 11 weeks. differentiated nail plate that emerges from ences between AEC and EEC are explained by underlying mutations in under the proximal nail fold during the fourth month of gestation and separate regions of the p63 gene. This constant alized. 12 and 14 weeks’ EGA. Encouragingly. for protein therapy. or EDAR-associated death domain (an intracellular adaptor entiated. the latter constitute the majority however. Unlike stem cells. Maternal hormones contribute to responsible for the X-linked variety of HED (XLHED). isotypes of the p63 protein. 63). The human epidermis renews itself every 40–56 days21. of ectodermal dysplasia. Nail development begins at 8–10 weeks’ EGA and is completed by the Clinical trials with recombinant EDA protein for the treatment of fifth month of intrauterine development. are found ventral to the proximal nail fold. of the future nail bed on the dorsal digital tips is first demarcated by In addition to mutations in genes that are required for appendage folds visible at 8–10 weeks’ EGA. with concomitant mainte. Underlying muta- 1 proliferative layer of the sebaceous gland generates lipogenic cells that progressively accumulate lipid/sebum until they are terminally differ- tions can occur in the genes encoding the EDA ligand. The curves and whorls formed by these ridges including craniofacial and skeletal defects. teeth. which is critical for the initiation of SECTION as the most superficial bulge on the developing hair follicle. Canaliza. Beginning between 14 and 16 weeks’ EGA. Canaliza. glands (hypohidrosis). The location of epidermal stem or more major ectodermal appendages (hair. where they affected15 (see Ch. and genetic defects in this pathway underlie conditions ranging from hereditary hypotrichosis simplex to onycho-odonto-dermal dys- Like hair and nails. The outer sweat gland. The glandular cords of cells elongate during the ensuing weeks. Because the underly- gland also has a disproportionately large zone of androgen production ing defect is in a soluble ligand that is only required for a brief period (referred to as the “fetal zone”). Wnt signaling is critical for the development of epidermal append- Eccrine and Apocrine Sweat Gland Development ages. cycle and move suprabasally. Stem cells are self-renewing and divide 16 weeks’ EGA. Mutations in p63. odontogenic keratocysts and multiple basal cell car- seen on the digit tips by the fifth month of gestation. stem cells are believed to tion of the epidermal component of the duct is not complete until 22 undergo asymmetric division. which initiates the keratinocyte terminal differentiation program. on the other TA cells and terminally differentiated cells are listed in Table 2. Ultimately. Apocrine glands function transiently during the third trimester turnover is mediated by epidermal stem cells. The neonatal adrenal lowing Blaschko’s lines in heterozygous females. which has important roles in neu- on the palms and soles between 55 and 65 days’ EGA. which affect different functions and completely covers the nail bed by the fifth month. The phenotypic differ- and replaced by the hard. at which time they disintegrate and release their products into protein that functions in EDAR signaling). 63). columns of cells composed of one disorders that are characterized by developmental abnormalities in two stem cell and its progeny (Fig. Under homeostatic conditions. EDA receptor (EDAR). The epidermis. palmoplantar eccrine sweat glands begin to develop plasia and Schöpf–Schulz–Passarge syndrome19. animals. The is caused by mutations in genes encoding components of the ectodys- presumptive sebaceous gland is first seen at around 13–16 weeks’ EGA plasin A (EDA) signaling pathway. portion of a hair follicle. The nevoid basal cell during the first trimester and are fully developed by the second trimes. instances. A wedge of ectoderm invaginates development. but there is some evi- 60 glands). hand. the mesenchymal pads in the human fetus regress by the third trimester. heterogeneous group of genetic dermal proliferative units (EPUs). dermis.

g. A Epidermal stem cells are located in the basal layer of the epidermis. B EPUs in human skin grafted onto the back of a nude mouse. TRANSIT AMPLIFYING CELLS AND TERMINALLY DIFFERENTIATED CELLS Stem cells Transit amplifying cells Terminally differentiated cells CHAPTER Self-renewal* Unlimited Limited No Potential for differentiation* Multipotent † Limited None 2  Cycling in normal epidermis Slow Rapid None Skin Development and Maintenance Proliferative potential (e. Whether these cells represent a separate stem cell population or whether they are derived from bulge stem cells (or vice versa) remains to be determined. cells24. upon division a stem cell gives rise to another stem cell and a cell that is destined to terminally differentiate (transit amplifying cell). 2. data suggest that palmoplantar epidermal stem cells are located at the potential as well as being self-renewing and multipotent. the expression of Lgr526. proliferate only when the hair follicle re-enters the active growing phase One distinguishing feature of stem cells is that they can be main. Holoclones can reconstitute epidermis in vitro. Reprinted with permission from Kolodka TM. they presumably represent stem after severe wounds such as second-degree burns. One of these populations is located in (see below). are summarized in Table 2. 61 Hair follicle bulge cells are slow-cycling and have a high proliferative follicular epidermis in response to injury25. EPUs were visible. In vivo. including their the lower outer root sheath in anagen hair follicles and is marked by molecular markers. Taichman LB (1998). A subset of epidermal keratinocytes was transduced with a β-galactosidase-expressing virus. The TA cells undergo a few rounds of cell division before they permanently withdraw from the cell cycle and initiate the terminal differentiation program. but still finite. allowing temporary reconstitution of the surface epidermis in vitro. the presence of EPUs indicates that they are derived from and maintained by epidermal stem cells. Table 2. 2. and it contains morphologically undifferentiated cells25. in which the bottom two-thirds of the follicle must be regen- tained in culture virtually indefinitely.g. of anagen. † Retention of a DNA label (e. referred to as holoclones. A subset of epidermal basal cells erated.S. Forty weeks after grafting these cells onto nude mice. © 1998 National Academy of Sciences. which is located in the mid portion of the follicle (just deep to the sebaceous gland and adjacent to the arrector pili Stem Cell Plasticity muscle attachment site). another stem cell and a transit amplifying (TA) cell are generated (asymmetry of fate). C With each cell division. Since only epidermal stem cells and not TA cells or differentiated cells are able to persist for this length of time. EPIDERMAL STEM CELLS A B C Cornified layer Granular layer Spinous layer Basal layer Differentiating cells Transit amplifying cells Stem cell Fig. transit amplifying cells and terminally differentiated cells. and they have In addition to bulge cells. they top of deep rete ridges. is thought to harbor hair follicle stem cells Under homeostatic conditions. 5-bromo-2-deoxyuridine or tritiated thymidine) is utilized as an in vivo marker of stem cells based on their slowly cycling nature. other cell populations in the hair follicle been utilized for the treatment of burns and inherited skin disorders display stem cell characteristics. during fetal development and wound healing) High Limited‡ None ‡ Growth in culture Sustained clonal growth Small abortive clones None Maintenance of tissue homeostasis Yes Limited No *In order to maintain both the stem cell and differentiating cell compartments. bulge-derived keratinocytes can also contribute to the repair of the inter. However. which is known as the epidermal proliferation units (EPU) (blue). ‡ The proliferative potential of transit amplifying cells of the matrix is higher than those of the interfollicular epidermis. the former cells can be serially passaged in culture.2  Properties of stem cells.4  Epidermal stem cells. Such appendageal stem cells provide an important ectodermal forms highly proliferative colonies that can be passaged long term reserve.3. Each epidermal stem cell and its progeny forms a vertical column of progressively differentiating cells.5). hair follicle. Evidence for keratinocyte stem cells in vitro: Long term engraftment and persistence of transgene expression from retrovirus-transduced keratinocytes Proceedings of the National Academy of Sciences of the United States of America 95:4356-4361.A. The properties of cutaneous stem cells. Hair Follicle Stem Cells The hair follicle bulge. this is referred to as asymmetry of fate. Garlick JA. Within the healing . epidermal and hair follicle stem (Fig. U. PROPERTIES OF STEM CELLS. The bulge represents the lowest permanent portion of the cells only contribute to their respective tissues of origin.

MCSP. Bulge many adult cells. CD200 Melanocyte§ Lower bulge and Hair matrix and Hair matrix and epidermal melanocytes Pax3. The treatment resulted in expression of functional laminin 332 and an absence of blistering in the corrected Hair follicle stem cells epidermis. LRIG1. chondrocytes “Dermal” Dermis (form spheres) ? In vitro: melanocytes. Induced pluripotent stem cells (iPS) are somatic cells (e. OCT4. SCA1. fibroblasts) that have been reprogrammed into an embryonic stem cell-like state28. NGFRp75. glycoprotein involved in cell adhesion and signaling. Schwann cells. both sustained over several years of follow-up. Clinical trials Melanocyte stem cells (in lowest permanent are also ongoing to investigate the value of bone marrow-derived stem portion of hair follicle) cell transplantation as a systemic treatment for the extremely severe recessive dystrophic form of EB (RDEB). SOX10. Treatment via delivery of gene- corrected stem cells has the advantage of continuous protein synthesis in the skin. laminin-β3-deficient skin from a man with junctional EB was corrected by transplantation of stem cell- enriched epidermal grafts transduced ex vivo with a retroviral vector Epidermal stem cells encoding normal LAMB3 cDNA. including different skin cell types. Stem Cell-Based Therapy for Genetic Skin Disease Stem cells have been utilized in several strategies for gene therapy of heritable skin diseases (Fig. VII deposition at the dermal–epidermal junction and variably decreased . CUTANEOUS STEM CELLS Stem cell Location (niche) Tissue regeneration in Tissue regeneration in injury repair Markers SECTION homeostasis 1 Keratinocyte   Interfollicular Basal layer Interfollicular epidermis Hair follicle Delta 1. stem cell antigen 1. leucine-rich repeats and immunoglobulin-like domains 1 (epidermal growth factor receptor antagonist and regulator of stem cell quiescence). leucine-rich repeat-containing G protein-coupled receptor 5/6. transferrin receptor. are able to incorporate themselves into diverse tissues (such as the epidermis or heart) and to adopt the fates of resident cells. marker of hematopoietic progenitor cells and endothelial cells. Schwann cells. Similarly. 2. BMI-1. TYRP2. tyrosinase. contrib- Dermis uting progeny to the tissue. tyrosinase-related protein. ‡ Upregulated in mouse bulge cells. family A. **Additional stem cell populations identified within the hair follicle in mice include LGR6-positive cells in the central isthmus and LRIG1-positive cells in the upper isthmus. LGR5.g. neurons. but it may carry a risk of oncogenesis (especially with retroviral vectors). follistatin. particularly bone marrow cells. † Within the outer root sheath just below the sebaceous gland. SCA1. SLUG. transmembrane glycoprotein that delivers a negative immunoregulatory signal (may be involved in maintaining immune tolerance). CD34‡. neurons. as they are rapidly replaced by progenies of epidermal stem cells. bone marrow transplantation after total or partial myeloablation resulted in 62 Fig. Some cell types. SLUG smooth muscle adipocytes. Interfollicular epidermis low levels of CD24. melanoma cell adhesion molecule/MUC18/S-Endo-1 antigen. SLUG. Note that the bulge is substantial proportions of donor cells in the skin. member1. CD24. epidermal stem Hair shaft cells can contribute to hair follicle formation in the center of large wounds27. Notch1 muscle. CD71. Table 2. nestin. Sebaceous gland PHLDA1. adipocytes. negative for KIT. PHLDA1. CD146   Sebaceous At or near the bud of the Sebaceous gland Sebaceous gland Blimp1 gland§ sebaceous gland Merkel cell Touch domes of hairy skin Interfollicular epidermis Interfollicular epidermis α6 integrin*. sebaceous gland stem cells have thus far been shown to be unipotent progenitor cells. § Studied primarily in mice.5  Keratinocyte and melanocyte stem cells. In an initial report29. CD200. ¶ Lowest permanent portion of the hair follicle. melanoma- associated chondroitin sulfate proteoglycan.6). CD71. Twist precursors” spheres) muscle adipocytes *Also expressed by epidermal transit amplifying cells. nerve growth factor receptor. at or near the site of insertion of the arrector pili muscle. KERATINOCYTE AND MELANOCYTE STEM CELLS epidermis. increased collagen continuous with the outer root sheath. Thus. may be capable of dedifferentiating into pluripotent stem cells. including keratinocytes. emerging data indicate that cells in adult mammals Epidermis are far more “flexible” in their potential to form other cell types than was previously thought. In a pilot study. low Overview of Basic Science epidermis Sebaceous gland levels of CD71 Interfollicular epidermis   Hair follicle** Bulge† Hair follicle Hair follicle Keratin 15. OCT4. both of which contribute to the interfollicular epidermis and sebaceous glands during homeostasis. smooth Nestin. smooth Twist. NGFR.3  Cutaneous stem cells. LGR5/6. LRIG1. α6 and β1 integrins. these cells can be stimulated to dif- ferentiate into a variety of cell types. chondrocytes “Skin-derived Dermal papilla (form ? In vitro: neurons. TYRP. bulge-derived cells survive only transiently. CD146. MCSP. 2. pleckstrin homology-like domain. Furthermore. frizzled homolog 1. CD34. CD200. α6* and β1 integrins. TYRP1 sub-bulge region¶ epidermal melanocytes “Neural crest-like” Bulge† (form spheres) ? In vitro: melanocytes.

could target stem cells that would supply the skin with the required protein blistering in children with RDEB. nosis and management of congenital skin disorders. Many genodermatoses are incompatible with survival to term or are technical difficulties (e. collagen gene ( ) recombination ( ) VII). the vector must target stem cells that could supply the protein to the Corrected epidermal skin.to ing the understanding of skin embryology may lead to life-saving or 63 10-cell) stage. Thus. useful far beyond the neonatal period. making prenatal diagnosis desirable. to sites of injury in patients with epidermolysis Transduce stem cells with bullosa) and produce differentiated progeny cells Correct genetic mutation virus encoding therapeutic by homologous that provide the needed skin protein (e. which are generated from somatic cells (e. D Finally. low rate of completed pregnancies. sex determination has been utilized both in conjunction with specific genetic analysis and to identify embryos of a particular sex for selective transfer. that result in the nevoid basal cell carcinoma syndrome. as many of the regula- ered. for long-lasting effects. In the early 1980s. Other investigators are studying for the known family mutation(s). A One strategy is to isolate epidermal stem cells from a patient. Preimplanta- PRENATAL DIAGNOSIS OF GENODERMATOSES tion genetic diagnosis obviates the need to terminate a pregnancy with an affected fetus. delineating the that allows for prenatal diagnosis before the embryo is implanted and factors involved in wound healing in embryos may point to interven- pregnancy begins.g. it has several disadvantages compared to chorionic villus sampling or amniocentesis. stem cells Corrected iPS cells Expand and graft back onto patient Differentiate corrected iPS cells into keratinocytes C Hematopoietic stem cells Corrected keratinocytes Obtain hematopoietic stem cells from matched donor Expand and graft back onto patient Hematopoietic stem cells D Direct delivery Expand and deliver Virus or other vector systemically to patient encoding a therapeutic following conditioning gene. sampling (10–12 weeks after the last menstrual period/8–10 weeks’ For example. however. which would then be differentiated into keratinocytes and grafted onto the patient. using a viral vector). C A third strategy involves the use of hematopoietic stem cells (HSC). including higher cost. and a associated with significant morbidity or even mortality after birth. therapeutic genes could be directly administered to patients via a virus or another vector. as these tech.6  Strategies for stem cell therapy of genetic STRATEGIES FOR STEM CELL THERAPY OF GENETIC SKIN DISORDERS skin disorders. B Gene therapy could also potentially utilize induced pluripotent stem (iPS) cells. contamination by extraneous DNA).g. The Herlitz form of junctional EB and epidermolytic hyperkeratosis were the first diseases Understanding skin development is essential for the appropriate diag- diagnosed prenatally using this technique. unaffected embryos are then selected alternative sources of stem cells for the treatment of EB.g. To achieve permanent correction. Upon systemic Patient epidermal administration (following conditioning). However.g. tions that may decrease scarring in children and adults. In addition to the germline PTCH mutations 14 weeks’ EGA) has largely replaced fetal skin biopsy. For X-linked disorders. somatic PTCH niques can be performed earlier and pose less risk to the mother and mutations represent a pathogenic factor in sporadic basal cell carcino- fetus. fibroblasts) the patient. The pathogenic mutation(s) must be identified in family members mas.g. allogeneic stem cells Patient iPS cells HSC cells have the capacity to home to the skin (e. intrauterine development holds promise for improving wound healing Preimplantation genetic diagnosis is a recently introduced technique and developing new anticancer therapies. for uterine implantation. This knowledge is As the causative genes for many genodermatoses have been discov. 2.g. Furthermore. The cellular DNA is amplified using PCR and analyzed life-enhancing therapies. Fig. and graft epithelial B Induced pluripotent stem cells sheets containing the corrected stem cells back onto CHAPTER Patient somatic cells (e. DNA-based testing using material obtained from chorionic villus tory pathways central to development are recapitulated in postnatal life. Fetal biopsies are typically obtained between 19 and 22 weeks’ EGA using ultrasound guidance and then analyzed SIGNIFICANCE OF SKIN DEVELOPMENT via light and electron microscopy for the characteristic morphologic IN POSTNATAL LIFE changes associated with the disease in question. . fetal skin biopsy became the first technique available for prenatal diagnosis of inherited skin diseases. correct the genetic defect   in vitro (e. One or two cells are taken from the embryo at the blastocyst (6. fibroblasts). PTCH is essential for postnatal hair cycling as well as EGA) or amniocentesis (14–16 weeks after the last menstrual period/12– hair follicle development. The 2  Skin Development and Maintenance Reprogram somatic genetic defect could be corrected via homologous A Epidermal stem cells cells into iPS cells recombination in these cells. This technique requires the use of in vitro fertiliza. Elucidation of the mechanisms controlling angiogenesis during prior to prenatal testing. advanc- tion.

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