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The Skin

The Skin

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ABSTRACT

Didactically, the skin is subdivided into 3 main layers. Each layer has a distinct cellular arrangement and physiology, which maintain tissue integrity. 

The 3 layers of the skin are: epidermis, dermis or corium, and subcutaneous fat layer or subcutis. 

  • The epidermis is the most external layer. It is comprised of 5 other layers, listed below from most superficial to deepest [1]:
    • Stratum corneum 
    • Stratum lucidum
    • Granular layer (stratum granulosum)
    • Spinosum layer (stratum spinosum)
    • Basal layer or basement membrane layer (stratum basale)
  • The dermis is further divided into papillary and reticular dermis:
    • Papillary dermis: upper layer, composed of loose connective tissue
    • Reticular dermis: deeper layer, consists of dense connective tissue. 
  • The subcutaneous layer is the innermost layer of the skin

This topic provides a practical overview of the main cell types and structures of each layer, including stem cells, appendages and nerves and their role in wound healing. For a review on principles of wound healing, see topic "Principles of Wound Healing"

INTRODUCTION

Overview

The skin is a versatile organ with several special characteristics. It is the interface between the individual and the external environment, and one of the largest organs of the human body, second only to the endothelium.[2] This topic provides an overview on the skin and its function and structure. For a review on principles of wound healing, see topic "Principles of Wound Healing".


FUNCTION

  • Protection: the skin represents the first line of defense against external elements (e.g. toxic substances, solar radiation, microorganisms, trauma, etc).[3]
  • Homeostasis: the skin helps maintain the water-electrolyte balance of the body, and plays a role in other functions, such as sensation, body fluid regulation, absorptive, thermoregulatory, immune regulation, and endocrine.[3][4]

STRUCTURE

  • Didactically, the skin is subdivided into 3 main layers. Each layer has a distinct cellular arrangement and physiology, which maintain tissue integrity (see Tables 1 and 2). 
  • The 3 layers of the skin are: epidermis, dermis or corium, and subcutaneous fat layer or subcutis (Figure 1). See more details below.

Fig. 1. Epidermis and dermis (histologic image)

Epidermis

  • The epidermis is the most external layer. It is comprised of 5 other layers, listed below from most superficial to deepest (see Figure 1) [1]:
    • Stratum corneum 
    • Stratum lucidum
    • Granular layer (stratum granulosum)
    • Spinosum layer (stratum spinosum)
    • Basal layer or basement membrane layer (stratum basale)
  • Common cell types in this layer: keratinocytes comprise between 80-95% of the cells in the epidermis (see Table 1). 
  • Blood supply: the epidermis does not have its own vascular system; it is nourished by diffusion of nutrients from dermal vessels
  • Innervation: only 5% of cutaneous nerve fibers reach the epidermis
  • Appendages: some cutaneous appendages originate from the epidermis and migrate to the dermis (e.g. hair, nails, sweat and sebaceous glands)

Dermis (or corium)

  • The dermis is located below the epidermal basal layer and is the thickest layer of the skin. The dermis consists mainly of connective tissue that provides strength and elasticity to the skin.[5] 
  • The dermis is further divided into papillary and reticular dermis:
    • Papillary dermis: upper layer, composed of loose connective tissue
    • Reticular dermis: deeper layer, consists of dense connective tissue. 
  • Common cell types in this layer: various cell types are present in the dermis, but only fibroblasts originate from this layer; in other words, fibroblasts are the only native cells of the dermis. The other cell types (e.g. inflammatory cells) have a migratory nature, and their numbers increase or decrease as needed during the wound healing process 
  • Blood supply: the dermis is well vascularized, with blood vessels that provide nutrients and remove waste for its own cells, as well as for the cells in the epidermis. Angiogenesis (i.e., formation of new vessels from existing vessels) is an important part of wound healing.[6] Angiogenesis is stimulated by certain growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (bFGF), platelet-derived endothelial growth factor, and others.[6][7][8]
  • Innervation: the dermis harbors sensory receptors (terminal endings of neural fibers) such as mechanoreceptors (touch, deep vibration and pressure), thermoreceptors (heat and cold) and nociceptors (pain and itch). There are also some fibers which have free endings in the skin, without receptors. See Figure 2 below.
  • Appendages: the dermis also hosts skin appendages - structures that are arranged and shaped to support the integrity of cutaneous tissue, among other functions. Examples include sweat and sebaceous glands and their hairs (pilo-sebaceous unit). See section 'Skin appendages and nerves' and Figure 2 below.
  • Lymphatic vessels: one of the 2 lymphatic plexuses of the cutaneous lymphatic system is located in the dermis near the blood vessels, while the other plexus is located in the subcutaneous layer.[9] The skin lymphatic system plays an essential role in regulation of interstitial fluid homeostasis and immune response. Furthermore, skin lymphatic vessels are involved in lymphedema, tumor metastasis, wound healing, psoriasis, and systemic sclerosis.[10][11]

Fig. 2. Cutaneous appendages and neural fibers

Subcutaneous fat layer

  • The subcutaneous layer is the innermost layer of the skin
  • Common cell types in this layer: adipocytes 
  • Function: conserves the temperature of the body, protects from injury, serving as a shock absorber

Epidermal and dermal cells

Table 1. Epidermal cells

Epidermal Cells Function and characteristics

Keratinocytes

[12][13][14] 

  • Account for about 80% of the cells of the epidermis 
  • Keratinocytes have high quantities of protein in their cytoplasm, which is mainly composed of keratin and keratohyalin (or filaggrin).
  • Function: keratinocytes give the epidermis structural and tensile strength 
  • Cell differentiation: keratinocytes originate in the basal layer and migrate to the stratum corneum over 45-70 days (the actual duration of this process may vary, being shorter in patients with psoriasis or longer in the elderly). As keratinocytes migrate, they mature and differentiate as follows:
    • Basal layer: keratinocytes originate from epidermal stem cells 
    • Stratum spinosum: keratinocytes differentiate into “squamous” or spinous cells, so called due to the presence of cytoplasmic extensions on the keratinocytes which resemble “spines”
    • Stratum granulosum: keratinocytes acquire granules in their cytoplasm
    • Stratum lucidum: intermediate layer before the stratum corneum, in palmar and plantar skin
    • Stratum corneum: keratinocytes undergo apoptosis and form the outermost layer of the skin. 

Melanocytes [15][16]



  • The second most common cell type in the epidermis, accounting for about 19% of the epidermal cell population.
  • Location: basal layer
  • Function: melanocytes play major roles in skin pigmentation, skin homeostasis and wound healing. Melanocytes may be considered as “cutaneous neurons”, due to their embryologic origin in the neural crest cells and other structural similarities such as cell bodies, axons, dendrites and synapses with neurotransmitters.

Dendritic cells (Langerhans cells) [17]

  • Make up about 1% of the epidermal cells
  • Function: The name and shape of these cells suggest a neural origin. However, they are of mesenchymal origin, being derived from macrophages. Dendritic cells are important for the immunologic function of the skin. 

Epidermal stem cells [18][19]

  • Epidermal stem cells (SC) are critical in skin homeostasis and wound healing. 
  • Different types of epidermal SCs reside in the following areas: in the interfollicular epidermis (iSCs), in the hair follicles (hair follicle SCs, hSCs), and in the sebaceous glands (sebaceous gland SCs, sSCs) or sweat glands. Each subtype of SCs regenerates the corresponding tissue and also substitutes for other subtypes during wound healing. 

Table 2. Dermal cells

Dermal CellsFunction and characteristics

Fibroblasts [20][21][22]

  • Fibroblasts are identified by their fusiform morphology, but they may come in diverse shapes, depending on their location and activity. 
  • Function: 
    • Fibroblasts maintain the structural integrity of connective tissue through the continuous formation and deposition of extracellular matrix (ECM) precursors. The composition of the ECM determines the physical and chemical properties of connective tissues.
      • Fibroblasts synthesize proteins (mainly collagen) of the extracellular matrix (ECM). Twenty eight subtypes of collagen have been identified. Their common structure resembles a triple helix composed of hydroxyproline, lysine and glycine. In the skin, the most common types of collagen are type I (80 to 85%), type III (10 to 15%) and type V in smaller quantities. 
    • Fibroblasts play an important role in wound healing: 
      • Upon skin damage, fibroblasts migrate to the site of the wound and initiate the process of collagen production and deposition. This process reaches its peak in the proliferative phase of scar formation.
      • Next, some fibroblasts develop actin and myosin filaments in their cytoplasm, changing into myofibroblasts. This occurs while the process of scar formation is in progress by the stimulus from Transforming Growth Factor beta (TGF-β) and mechanical stretch signals (mechanoreceptors).
      • Myofibroblasts form the granulation tissue in combination with vascular proliferation (neovascularization). Finally, myofibroblasts have a contractile property, helping  reduce the size of the original wound 

Dermal stem cells [18]

  • Dermal SCs reside in hair papilla or among other dermal cells, and they can differentiate into pericytes, fibroblasts, myoblasts, or chondrocytes.

Monocytes [23]

(non-native to the dermis)

  • Monocytes make up 2-8% of white blood cells.
  • Function: monocytes circulate in the bloodstream and quickly move to the injured skin through a movement known as diapedesis. Once in the skin, monocytes differentiate into macrophages and dendritic cells.
  • Macrophages have the ability to phagocytose foreign substances in the body, promoting antigen presentation and producing cytokines and growth factors.

Mastocytes [24][25] 

(non-native to the dermis)

  • Mastocytes originate from precursor cells in the bone marrow, and are released into the bloodstream in an immature form. From the bloodstream, mastocytes arrive in other tissues through diapedesis, where they undergo maturation.
  • Function: although mastocytes play a role in allergic reactions, mastocytes serve an important function wound healing. 
    • Monocytes have cytoplasmic histamine and heparin granules. When activated, monocytes release their granules and diverse hormonal mediators into the interstitium. This degranulation can be triggered by a direct skin lesion, cross-linking of immunoglobulin E (IgE) receptors or by activation of the proteins of the complement system.

Neutrophils [26]

(non-native to the dermis) 

  • Neutrophils are the most numerous cell type among white cells, and are subdivided into band and segmented neutrophils. Mastocytes arrive through the bloodstream and infiltrate other tissues through diapedesis. 
  • Function: promptly activated after a lesion or injury, neutrophils play an important role in the inflammatory phase of wound healing. 

Stem cells

  • Stem cells (SC) play an essential role in wound healing. SCs are characterized by their potential for self-renewal and differentiation into other cell types. Skin SCs consist of epidermal SCs, dermal SCs, and melanocytic SCs.[18]
  • Other SC that are usually present in the circulation migrate to the skin when an injury occurs. As a result, the main types of stem cells involved in the wound healing process are: epidermal and dermal SCs, mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs) and hematopoietic stem cells (HSCs).[27]
  • SCs help promote wound healing by several mechanisms, such as stimulation of resident cells, release of growth factors, control of inflammation and remodeling of extra-cellular matrix.[27] 
  • Several pre-clinical studies have shown that stem cell therapy with adipose-derived stem cells, epidermal stem cells, hair follicle stem cells and other SC can promote wound healing, mainly through angiogenesis and anti-inflammatory actions.[28][29][30][27] 

Skin appendages and nerves

Primarily located in the dermis, skin appendages and nerves are essential for fully functional skin. Skin appendages include sweat glands, hair follicles and sebaceous glands (i.e., a pilosebaceous unit). The recovery of skin sensory function is an important indicator of cutaneous regeneration.[3] See Table 3, and Figures 2 and 3.

Table 3. Cutaneous appendages and nerves

Cutaneous appendages
Function and characteristics

Sweat glands

[31][32] 

  • Location: Distributed over the entire body surface, except in the glans and lips.
  • Function: sweat is produced and secreted by the gland onto the skin surface through its orifice. 
  • Types:
    • Eccrine glands: have excretory ducts that open directly into the pores of the cutaneous surface. 
    • Apocrine glands are present in the axilla, genital area, nipples and on the male face. Their content is secreted along the length of the hair follicle.
    • Apoeccrine glands have characteristics similar to the first two types and are found in the axilla. 

Pilosebaceous unit [18][33][34] 



  • The pilosebaceous unit is formed by a hair follicle and its corresponding sebaceous gland. It has its own vascular and neural components. 
  • Function: 
    • Mature cells undergo apoptosis and their lipid content made up of sebum is excreted. Sebum is composed mainly of lipids, triglycerides, free fatty acids, esters, cholesterol and squalene. Sebum acts as a mechanical and functional barrier and contributes to antimicrobial activity.
    • The follicular bulge of the pilosebaceous unit contains mesenchymal stem cells that are responsible for hair growth, and participate in epithelialization and wound healing. Melanocytic SCs are undifferentiated melanocytic cells located in hair follicles that differentiate into melanocytes during each hair follicle cycle.

Neural fibers

[35][36][37]

  • The skin has a peripheral nervous system with sensory, sympathetic and parasympathetic innervation. See Figure 3 below.
  • Types: 
    • Aβ fibers: myelinated, fastest neural impulse conduction, responsible for tactile sensation
    • Aδ fibers: myelinated, respond to nociceptive stimuli such as cold and pressure (provide fast/first pain information)
    • C fibers: unmyelinated, slowest neural impulse conduction, respond to temperature and pain stimuli (nociceptive). Type C fibers are also related to inflammation.
  • The endings of these neural fibers in the dermis have sensory receptors classified as mechanoreceptors (touch, deep vibration and pressure), thermoreceptors (heat and cold) and nociceptors (pain and itch). There are also some fibers which have free endings in the skin, without receptors. Thermoreceptors and nociceptors are involved in wound healing.
Fig. 3. Schematic of histological cut of the skin showing neural fibers. The Aδ fibers are represented by the continuous line of greater diameter and are located in the dermis, near the basement membrane. The C fibers are represented by the thinner continuous line and prologue to the epidermis. The autonomic fibers are represented by the thin and dotted line, innervating the cutaneous attachments and vessels in the subcutaneous tissue. 
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