ABSTRACT

Besides its key physiological functions as a stable, waterproof barrier adapted to withstand a variety of physical, chemical, and biological insults, the epidermis also plays major psychological and social roles, in particular with respect to appearance and social acceptance as well as non-verbal communication. However, its strategic location at the direct interface between the external and internal environments makes the epidermis particularly prone to a wide variety of disorders that can compromise both its physiological and psychological functions, sometimes dramatically so. Hence, understanding epidermal homeostasis has long been highly desirable for a wide variety of therapeutic and cosmetic applications. However, to be productively achieved, such an understanding must be undertaken from a holistic basis, which, in turn, requires a systems-based analytical approach (systems biology). But the task entails more difficulties than might appear at first sight. Even if reduced to

its simplest possible representation (dermal-epidermal junction + stratified keratinocytes undergoing terminal differentiation + melanocytes that may or not be synthesizing melanin and transferring melanosomes to keratinocytes), the variety of biological processes and regulatory mechanisms intimately involved is daunting and, in their vast majority, cannot be reduced to, let alone be manipulated through, gene-based interaction networks, thereby precluding classical systems approaches.This chapter provides an overview of the problems that must be solved and describes the logic and working principles behind a systems-based approach that has proven its efficacy in various medical and biological fields. The closing sections are devoted to a brief demonstration of how this approach can be implemented by proposing a detailed analytical reconstruction of the mechanisms that could sustain a still largely obscure aspect of epidermal homeostasis. 15.1 IntroductionSkin, the largest organ of the human body, structurally consists of three compartments, which differ in function, structure, and embryological origin. The outer compartment, or epidermis, is formed by a non-vascularized epithelium of ectodermal origin [15]. The underlying thicker compartment, the dermis, consists of fibroblasts embedded in connective tissue. It is vascularized and originates from the mesoderm. Epidermis and dermis are separated by a complex basement membrane, the dermal-epidermal junction (DEJ), which results from interactions and cross-talks between fibroblasts and keratinocytes [18]. The DEJ tightly binds the epidermis to the dermis and provides an adhesive and dynamic interface. It determines the polarity of basal keratinocytes, the spatial organization of keratinocytes and epidermal architecture. Epidermal stratification proceeds with the proliferating keratinocytes remaining attached to the basement membrane and the daughter cells migrating towards the upper layers [20]. The DEJ constitutes the intermediate anchorage zone for the anchoring filaments originating from the epidermis and the anchoring fibrils stemming from the fibrillar dermis. The DEJ also plays key regulatory role in the segregation and delivery of growth factors, cytokines and signalling effectors of dermal and vascular origins to basal and

supra-basal keratinocytes as well as to melanocytes and resident immunological components [22].Beneath the dermis resides a subcutaneous loose connective tissue, the hypodermis or subcutis, which binds the skin to underlying structures (muscular fascia). Hair follicles, sweat glands and sebaceous glands are of epithelial origin and are almost systemic appendages of the skin. 15.2 Structural and Functional Characteristics

of the EpidermisStructurally, the epidermis is characterized by a highly deceptive apparent simplicity. Yet, the epidermis, detects, integrates, and re-sponds to a wide range of external factors. It also has immunological functions and provides some protection against ultraviolet radiation via induced or constitutive pigmentation. These functions are met by its particular histological organization, a multi-stratified squa-mous epithelium, generated by the keratinocytes through a tightly regulated differentiation process, called epidermal terminal differentiation or keratinization [23]. Most of the relevant information relative to epidermal stratified structures is given in previous chapters as well as below, and only a brief overview concerning the role of skin appendages, which play a considerable role in overall epidermal homeostasis, will be provided in this section.One characteristic feature of the human skin is the apparent absence hair (pili) on most of the body surface. Nevertheless, most of the skin actually bears hair, which, in most areas, are short, thin and lightly pigmented. Only palms and soles, phalanges and sides of fingers, toes and parts of the external genitalia are truly hairless. Each hair follicle is associated with a sebaceous gland, forming a pilo-sebaceous unit. The lipid secretion of sebaceous glands (sebum) shows antibacterial and antifungal activity thereby selecting a resident lipophilic flora. It also contains proteases [24].Two types of sweat glands are also present in human skin, distinguished by (i) their secretory mechanisms into eccrine (merocrine) and apocrine sweat, (ii) the composition of excreted sweat, and (iii) their structures, where the apocrine duct, contrarily to that of eccrine glands, admix within the pilo-sebaceous canal, i.e., with sebum.