DERMIS

The dermis is one of the three constitutive layers of the skin, situated between the epidermis   and the hypodermis  , and is composed of two layers, the papillary dermis lying immediately below the epidemis and the reticular dermis. It is a 2 to 4 mm-thick layer of connective tissue mainly composed of extracellular matrix (ECM) produced by fibroblasts.

The dermis houses vascular and lymphatic vessels, nerves and specialised neural receptors which include sensory nerve receptors of Merkel and Meissner’s corpuscles (for touch), Pacinian corpuscles   (for pressure), and Ruffini corpuscles   (mechano-receptors). The dermis contains also epidermal appendages including eccrine and apocrine sweat glands, pilo-sebaceous follicles. The dermis also hosts multifunctional cells of the immune system such as dendritic dermal cells, macrophages   and mast cells   .

The dermis is divided into two functional layers, the papillary dermis and reticular dermis which differ in both the composition and organization of their respective extracellular matrices. The reticular dermis is characterized by thick well-organized fiber bundles which contrast with the thin, poorly organized collagen fiber bundles of the papillary dermis, consisting primarily of type I and type III collagens. Collagen fiber bundles in the papillary dermis contain more type III collagen than do those in the reticular dermis

 1. Resident cells of the dermis

Cells are more numerous in the papillary dermis than in the reticular dermis and form two sub-populations. The first one includes the fibroblasts and the fibrocytes   which, by producing the extracellular matrix, supply the basic structure of the dermis. The second one consists of hematopoietic cells, namely the dermal dendritic cells, the macrophages and the mast cells which are dermal representatives of the immune system.

 1.1 Fibroblasts

Fibroblasts are the main cells of the dermis and represent a heterogeneous population of cells with distinct patterns of synthetic activities and functions (Sorrell and Caplan, 2004), and the conventional understanding of these cells, which is based largely on cell morphology is inadequate. In addition to fibroblasts that remain during embryonic development, BM appears to be an important source that provides ‘‘fibroblasts’’ to the skin in adults, which may include, but is not limited to, CD45-negative mesenchymal stem cells   (BM-MSCs), CD45-positive fibrocytes and endothelial progenitor cells (EPCs ). The role of these newly discovered components of ‘‘fibroblasts’’ in the dermis are not fully understood. BM-MSCs and EPCs are thought to enhance cutaneous repair/regeneration and fibrocytes appear to cause fibrosis and are probably involved in hypertrophic scar formation.

Three subpopulations of dermal fibroblasts have been defined according to their location in the papillary dermis, in the reticular dermis or associated with the hair follicle, lying in the dermal papilla or along its shaft. In cell culture, papillary fibroblasts divide at faster rates than do site-matched reticular fibroblasts. Reticular dermal fibroblasts seeded into type I collagen lattices contract them faster than do papillary dermal fibroblasts. In monolayer culture, at confluence, papillary fibroblasts attain a higher density than do reticular fibroblasts.

The proteoglycan decorin   is intensely expressed in the papillary dermis but is dispersed between collagen fiber bundles in the reticular dermis. In monolayer cultures, papillary dermal fibroblasts secrete significantly more decorin and contain more decorin mRNA than did corresponding reticular cells. By contrast, the two cellular populations produce identical amounts of biglycan.

The main function is to synthesize or degrade the extracellular matrix and the extrafibrillar matrix; they also play a key role in dermo-epidermal interactions. It has been shown that the same fibroblast is able to synthesize more than one type of collagens and elastin simultaneously.

Fibroblasts cooperate with keratinocytes to organise the dermal-epidermal junction. Both produce type IV collagen, a major component of the lamina densa and type VII collagen the main component of the anchoring fibrils. The fibroblasts is also a major source of entactin  /nidogen.

 1.2 Resident dermal cells of the immune system

 1.2.1 Macrophages

Macrophages are derived from the bone marrow. They differentiate into monocytes in the blood, then become terminally differentiated in the dermis as macrophages with no more ability to divide. They are able to phagocyte cellular debris and pathogens, process (digest) them and present antigens to lymphocytes and other immune cells to trigger a specific immune response. Macrophages are also secretory cells vital for the regulation of immune responses and the development of inflammation  ; they produce hydrolytic enzymes, components of the complement system, and a variety of soluble factors such as interleukin-1, certain prostaglandins, interferon, growth promoting factors, .... They also express at their surface receptors for lymphokines that allow their activation.

 1.2.2 Dermal dendritic cells

Dermal dendritic cells (DDC) were identified more than 120 years after LCs were discovered. Initially, DDC were identified using a polyclonal antibody against clotting factor XIIIa and thought to be a homogeneous population. Dermal DCs are located in the deeper dermis. They typically express the C-type lectin, CD 209 (DC-SIGN), and CD11b, both of them are absent from Langerhans cells  .
Dermal, dendritic, antigen-presenting cells may elicit immune responses to cutaneous or circulating antigens and may form an important second line of defense behind epidermal Langerhans cells.

Dermal dendritic cells have the capacity to take up cutaneous antigens, mature and migrate to draining local lymph nodes, and present these antigens to T cells and B cells.. This process may be essential during skin infections, such as herpes simplex, as blockade of dermal DC migration from skin to lymph node may prevent effective cytotoxic T cell activation.

 1.2.3 Plasmacytoid dendritic cells

Plasmacytoid dendritic cells (PDCs) are an additional unique population of resident cutaneous DCs. They have a morphology, which is similar to a plasma cell and share many characteristics with B cells, including dependence on a B cell transcription factor (SPI-B), and immunoglobulin gene rearrangements. Both PDCs and myeloid DCs may arise from a bone marrow-derived common DC precursor. Plasmacytoid DCs express high levels of HLA-DR, have the capacity to present antigen, and are characterized by their ability to produce large amounts of type 1 interferon (IFN-α, β, ω) during viral infection (10,000 fold more IFN than any other cell type).

 1.2.4 Mast cells

Mast cells are specialized secretory cells that contains many granules rich in histamine   and heparin and are present throughout the dermis but found most commonly around blood vessels, pilosebaceous apparatus and in the subcutaneous fat (hypodermis).

Mast cells respond to physical stimuli (ligth, cold, heat, acute trauma, vibration, and sustained pressure), chemical and immunologic stimuli by releasing the content of their secretory granules. The granule release firstly induces vasodilatation, dermal edema then an infiltration into the dermis of inflammatory cells (neutrophils, eosinophils and basophils), attracted by the released chemotactic factors. Mast cells are the sentinel cell in immediate-type hypersensitivity reactions and are also involved in the production of subacute and chronic inflammatory diseases.

Mast cells stain metachromatically with toluidin blue stain, and immunohistochemically with antibodies to chymase and tryptase. They also express the c-kit protein. At the ultrastructural level, the granules can be easily separated into secretory and lysosomal granules.

 2. The ExtraCellular Matrix (ECM)

The extracellular matrix is a complex structure composed of highly organized collagen, elastic, and reticular fibers.

Type I collagen is by far the most abundant protein in human skin, comprising greater than 90% of its dry weight. Fibrillar collagens type I, III, and V self assemble into larger collagen fibers that form a three dimensional structural network throughout the dermis and provide the skin with tensile strength and tissue integrity. The collagen network is organized and maintained by dynamic mechanical tension provided by the fibroblasts responsible for its production .

All fibrillar collagens consist of three polypeptide chains wound around each other in a triple helical configuration. Each polypeptide chain is originally synthesized with additional amino acids at both ends that confer solubility. The soluble triple helix, which is termed procollagen, is assembled inside fibroblasts. Procollagen is secreted from fibroblasts, and the peptide ends are removed by two enzymes in the extracellular space. Removal of the ends produces collagen, which spontaneously assembles into large fibers that are enzymatically cross-linked.

Elastic fibres, responsible for the retractile properties of the skin, can be visualised with histochemical stains (orcein). Three different classes of elastic fibre, named oxytalan fibres, elaunin fibres, or elastin fibres have been distinguished according to their content in microfibrils, made of fibrillin, and in elastin, an additional amorphus component . Oxytalan fibres are localised in the papillary dermis and contains only microfibrils (10–12 nm across). They form arborisations that are perpendicular to the dermal-epidermal junction. Elaunin fibres and elastin fibres contain respectively either a little or a lot of additional amorphous components. Elaunin fibers are organised in a sub-papillar plexus that runs horizontally and is anastomosed with the oxytalan fibers and the thicker elastin fibers of the reticular dermis.

It is elastin that provides elasticity and resiliency of the elastic fibers and helps skin to return to its original position when it is poked or pinched. The microfibrillar part of the elastic fibre is composed principally of fibrillin-1a large glycoprotein more than 2800 amino acids long and with Ca2+ binding repeats that aid stabilization of the molecule. Elastic fibres are designed to maintain elastic function for a lifetime. However, various enzymes (matrix metalloproteinases and serine proteases) are able to cleave elastic fibre molecules. Indeed, loss of elasticity due to degradative changes is a major contributing factor in degenerative changes in sun-damaged skin.

The reticular fibers are fibers composed of type III collagen that are observed in histology after a silver staining, at the dermal-epidermal junction and in the basal lamina of blood vessels, nerves and adipocytes.

 3. The extrafibrillar matrix

The dermal material lying outside the
cells, and not consisting of either collagen fibres or elastic
fibres, is called the extrafibrillar matrix, which is extracellular and composed of a complex mixture of proteoglycans, glycoproteins, glycosaminoglycans, water, and hyaluronic acid. Chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, and heparin are the most significant glycosaminoglycans, which, bound to proteins, form the proteoglycans of the skin. Versican   and perlecan   are the most important proteoglycans of the skin; versican produced by fibroblasts, smooth muscle cells and epithelial cells is involved in assuring the tautness of the skin; perlecan is found in basement membranes. Other major glycoproteins are laminins, matrilins  , vitronectin  , thrombospondins, fibronectin, and tenascins  ; they are involved in cell adhesion, cell migration, and cell-cell communication.

Bibliography

Desmond J. Tobin: Biochemistry of human skin—our brain on the outside. Chem. Soc. Rev., 2006, 35, 52-67