The Ontogeny of Skin

Abstract

Significance: During gestation, fetal skin progresses from a single layer derived from ectoderm to a complex, multi-layer tissue with the stratum corneum (SC) as the outermost layer. Innate immunity is a conferred complex process involving a balance of pro- and anti-inflammatory cytokines, structural proteins, and specific antigen-presenting cells. The SC is a part of the innate immune system as an impermeable physical barrier containing anti-microbial lipids and host defense proteins. Postnatally, the epidermis continually replenishes itself, provides a protective barrier, and repairs injuries. Recent Advances: Vernix caseosa protects the fetus during gestation and facilitates development of the SC in the aqueous uterine environment. The anti-infective, hydrating, acidification, and wound-healing properties post birth provide insights for the development of strategies that facilitate SC maturation and repair in the premature infant. Critical Issues: Reduction of infant mortality is a global health priority. Premature infants have an incompetent skin barrier putting them at risk for irritant exposure, skin compromise and life-threatening infections. Effective interventions to accelerate skin barrier maturation are compelling. Future Directions: Investigations to determine the ontogeny of barrier maturation, that is, SC structure, composition, cohesiveness, permeability, susceptibility to injury, and microflora, as a function of gestational age are essential. Clinicians need to know when the premature skin barrier becomes fully competent and comparable to healthy newborn skin. This will guide the development of innovative strategies for optimizing skin barrier development.

Figures

Marty O. Visscher, PhD

Figure 1.

Electron micrographs of skin samples from a premature infant at 26 weeks of gestation.(A) The image shows the basal, spinous, and granular layers and a few layers of SC. The keratohyalin granules in the upper granular layer can be seen. (B) The stratum corneum is five layers thick at this time. Used with permission from Holbrook and Odland. SC, stratum corneum.

Figure 2.

Skin structure and function. The human epidermis evolves during gestation to form a well-designed, structurally sophisticated, integrated, cohesive, and protective tissue composed of four major layers, that is, basal, spinous, granular, and SC (cornified). Within the spinous and granular layers, the cells are attached to each other via desmosomes, protein-based structures that interconnect the layers of the epidermal barrier. A wound can be defined as a “breach of the integument, beginning at the SC” and/or any change that disrupts the normal structure and homeostasis. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 3.

Forms of epidermal innate immunity. The skin provides innate immunity via several mechanisms. Structural proteins throughout the skin (C) form the highly structured physical barrier and include collagen in the dermis (1), integrin (2), transglutaminases (3), desmoplankin (4), keratin 1,10 (5), involucrin (6), filaggrin (7), and loricrin (8). Sebum, sweat, and fatty acids on the skin surface (A) provide antimicrobials. The SC (B) contributes structural integrity via barrier lipids, corneodesomosones, and the antimicrobials lysozyme and lactoferrin. Lipids in the lamellar bodies (D) produce SC lipids. Antimicrobial and wound repair properties are conferred by the cytokines and proteins of the differentiating keratinocytes (E). Langerhans cells (LCs) (F) defend the organism if the SC barrier is breached. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 4.

SC architecture. During the final trimester, a remarkable process of epidermal differentiation culminates in formation of the SC. The SC is in direct contact with the environment, making it the first line of defense and consists of ∼16 corneocyte cell layers that are embedded in the lipid matrix. Lipids are synthesized in the nucleated cells of the epidermis and stored in lamellar bodies in the spinous layer. They are secreted from the lamellar bodies into the intercellular spaces at the interface between the granular layer and the SC. The thickness is 10–40 μm, varying with anatomical location. The corneocytes are interconnected within and between layers via corneodesmosomes. The protein filaggrin undergoes proteolysis to form NMF, which is responsible for SC hydration, water-handling properties, and plasticity. By design, the SC structure is mechanically tough and difficult to penetrate from the outside. NMF, natural moisturizing factor. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 5.

Epidermal lipid composition during gestation. (A) The epidermal lipid composition is relatively constant from week 8 through week 16. By week 19, the fraction of sterol esters/wax esters is substantially higher, and triglyceride levels increase. The sterol esters and wax esters increase between 14–17 and 20–28 weeks. (B) Sterol esters/wax esters and ceramides increase, and fatty acids decrease over the period.

Figure 6.

Vernix caseosa formation. Vernix lipids include types produced by the sebaceous glands. Vernix is extruded out through the hair shaft and onto the interfollicular epidermis, eventually spreading over the entire surface throughout gestation. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 7.

Full-term infant skin adaptation. (A) TEWL is very low at birth, equal to or lower than adults, indicating a highly effective skin barrier. (B) Hydration decreases rapidly during the 1st day and then increases during the 1st 2 weeks, in contrast to constant hydration in maternal skin.(C) The water-binding free amino acids (constitutes 40% of the NMF) are extremely low at birth, increase over the 1st month in parallel with increased hydration, but remain markedly lower than adult levels. *Indicates significant differences among all three groups. TEWL, transepidermal water loss. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 8.

Premature infant skin and adaptation. (A) The extent of epidermal barrier maturation depends on GA at birth. At 23 weeks, the SC is nearly absent with TEWL values that are similar to what they would be in an open wound.(B) The TEWL remains significantly higher for premature infants versus normal full-term infants even 1 month after birth.(C) The immature SC of premature infants is functionally compromised for several weeks after birth with estimates of full maturation time varying from 2 to 9 weeks of postnatal age. GA, gestational age. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 9.

Biomarkers of innate immunity in premature infants, full-term infants, and adults. (A, B) Neonates ≤32 weeks of GA had higher levels of involucrin and albumin than full-term infants and adults (p<0.05). * indicates significant difference from all, and ** from adults. (C) Keratin 1,10,11 was lower in both infant groups than adults. *Indicates significant difference from all. (D) The proinflammatory cytokine IL1α was higher in both infant groups than adults and higher in premature than full-term infants when adjusted for GA. #Indicates significant difference from adults, and * from full-term infants. (E) The premature infants had higher levels of the proinflammatory cytokines interleukin 6, interleukin 8, interleukin 1 beta, and monocyte chemotactic protein-1 than full-term infants and adults. #Indicates significant difference from full-term infants, and * from all.