| Dermal Cells | Function and characteristics |
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Fibroblasts [15][24][25][26][27][28][29][30]
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- Fibroblasts are identified by their fusiform morphology, but they may come in diverse shapes, depending on their location and activity (Figure 5).
- Fibroblasts are mesenchymal cells derived from the embryonic mesoderm tissue. Fibroblasts can be activated by a variety of chemical signals that promote proliferation and cellular differentiation to form myofibroblasts, which have contractile properties.
- Function:
- Fibroblasts maintain the structural integrity of connective tissue through the continuous formation and deposition of extracellular matrix (ECM) precursors. The ECM is a non-cellular structure that serves as a scaffold for cellular function; its composition determines the physical and chemical properties of connective tissues.
- Fibroblasts synthesize proteins of the ECM. Those proteins include collagen, elastin, reticulin, proteoglycans and glycosaminoglycans.
- Collagen is the main type of protein synthesized by fibroblasts; it constitutes the main structural protein of the body (Figure 5). Twenty eight subtypes of collagen have been identified. Their common structure resembles a triple helix composed of hydroxyproline, lysine and glycine. The five major types of collagen are:
- Type I: most common type of collagen in the skin (80 to 85%), along with type III (10 to 15%) and type V in smaller quantities. Predominant type of collagen in keloids.[30]
- Type II: found in cartilage
- Type III: the main component of reticular fibers. Predominant type of collagen in hypertrophic scars.[30]
- Type IV: found in basal lamina (i.e., layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits; part of the basement membrane)
- Type V: found in cell surfaces, hair and placenta
- Elastin is the highly elastic connective tissue protein that allows tissues to resume their shape after being stretched.
- ECM aids in cellular adherence, tissue anchoring, cellular signaling, and recruitment of cells. Upon acute or chronic cutaneous injury or damage, the ECM is also damaged. Through a series of overlapping events called the wound healing phases - hemostasis, inflammation, proliferation, and remodeling - the ECM is synthesized and ideally returned to its native state. See topic "Principles of Wound Healing"
- Cellular adhesion within ECM is mediated through cellular adhesion molecules (CAM). CAM proteins are cell surface proteins that mediate the interaction between cells, or between cells and the ECM. CAM are generally divided into five groups: integrins, selectins, cadherins, members of the immunoglobulin superfamily (IgSF) and others such as mucins.[24]
- Fibroblasts play an important role in wound healing:
- Upon skin damage, fibroblasts are attracted to the wound environment by chemoattractants, such as platelet-derived growth factor (PDGF), interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), secreted by platelets and macrophages. Fibroblasts migrate to the site of the wound and initiate the process of collagen production and deposition, which reaches its peak in the proliferative phase of scar formation. Fibroblast proliferation is stimulated by multiple growth factors (e.g. PDGF, EGF, FGF) and hypoxia at the center of the wound. As neovascularization occurs, the hypoxic stimulus for fibroblast proliferation decreases.
- Next, some fibroblasts develop actin and myosin filaments in their cytoplasm, changing into myofibroblasts. This occurs in granulation tissue 3-5 days after initial wounding, while the process of scar formation is in progress by the stimulus from Transforming Growth Factor beta (TGF-β), PDGF, ED-A fibronectin 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.
- In pathological wound healing (i.e. hypertrophic scarring), myofibroblast activity persists, which results in tissue deformation and severe contractures.
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Dermal stem cells [22]
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- Dermal SCs reside in hair papilla or among other dermal cells, and they can differentiate into pericytes, fibroblasts, myoblasts, or chondrocytes.
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T lymphocytes (T cells) [15][31]
(non-native to the dermis) | - The final cells recruited during inflammation are lymphocytes, attracted by several chemoattractants including IL-1.[15][31] While T cells have been regarded as arriving late in the inflammatory process, it has been shown that T cells are present in murine wounds within 24 h of wounding and remain present for at least 30 days.[31]
- Function: It is believed that T cells likely not only play an important role in regulating the inflammatory response but may also continue to modulate cells in the wound.
- Lymphocytes can be divided into two major classes: T, or thymic-derived, and B, or bone marrow-derived, lymphocytes.[31]
- Activated B cells (B lymphocytes) mature into plasma cells that produce antibodies
- Activated T cells differentiate into unique phenotypic subtypes, such as:
- CD3+ T cells can be subdivided into CD4+ and CD8+ T cells:
- CD4+ T cells (helper T cells) : produces cytokines that modulate both innate and adaptive immune responses (e.g. activate macrophages or B lymphocytes).
- CD8+ T cells (cytotoxic T cells): produces some inflammatory cytokines, but their primary active function is cytotoxicity (i.e., directly target and kill antigen-bearing cells)
- Suppressor T cells: downregulates inflammation and proliferation as the wound matures
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Mastocytes (mast cells) [32][33][34] (non-native to the dermis) | - Mastocytes (mast cells) 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 reside and undergo maturation.
- Two types of mast cells have been identified: the connective tissue type and mucosal type (majority of mastocytes).
- The cytoplasm of the mast cell contains 50-200 large granules that store inflammatory mediators, including histamine, heparin, serotonin, eicosanoids, chondroitin sulfate, a variety of cytokines, and neutral proteases.[32]
- Function: although mastocytes play a role in allergic reactions, mastocytes serve an important function wound healing.
- Mastocytes have cytoplasmic granules. When activated, they release histamine, eicosanoids, and vasoactive proteins that result in immediate vasospasm and subsequent vasodilation and leakness of vessels at the wound site. This degranulation can be triggered directly by pathogen binding, or indirectly through cross-linking of immunoglobulin E (IgE) receptors or by activation of the proteins of the complement system.
- Granules also contain proteolytic enzymes that have a role in cellular recruitment and activation of endothelial cells.
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Monocytes and macrophages [15][35][36]
(non-native to the dermis)
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- Monocytes make up 2-8% of white blood cells.
- Function: monocytes circulate in the bloodstream and upon signs of local tissue hypoxia, quickly move to the injured skin through a movement known as diapedesis. Arrival of monocytes and T-lymphocytes in the wound are the first overlap of steps between hemostasis and inflammation.[15] Once in the skin, monocytes differentiate into macrophages and dendritic cells.
- The presence of macrophages in the wound mark the transition between the inflammatory and proliferative phases of healing. They peak in the wound at about 48-72 hours and are the predominant cell population in the wound until fibroblast migration and replication occur during the proliferative phase.
- Macrophages have the ability to phagocytose foreign substances in the body, promoting antigen presentation and producing cytokines, complement proteins, reactive oxygen species, protease inhibitors and growth factors (TNF-alpha, TNF-beta, IL-1, IL-6, PDGF, TGF-alpha, TGF-beta). Hypoxic environments (e.g. wound) stimulate macrophages to promote angiogenesis.[36]
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Neutrophils [15][37]
(non-native to the dermis)
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- Neutrophils are the most numerous cell type among white cells. They account for approximately 50-70% of all white blood cells (leukocytes) and are subdivided into band and segmented neutrophils. Neutrophils arrive through the bloodstream and infiltrate other tissues through diapedesis; they peak at 48 hours post wounding.
- Function: promptly activated after a lesion or injury, neutrophils are recruited to the wounded site by PDGF and TGF-β and are the first inflammatory cells to arrive.[15] They serve as the first line of innate immune defense and play an important role in the inflammatory phase of wound healing (Figure 7).
- The primary function of infiltrating neutrophils is to remove foreign or damaged particles, bacteria, and non-functioning host cells found in the wound.[15] Neutrophils accomplish this function through phagocytosis, degranulation, and the production of chromatin and protease traps.[15] During degranulation, neutrophils engulfs and degrades bacteria and debris through release of several toxic enzymes. The resulting debris either becomes part of the scab and is sloughed off or phagocytized by macrophages.
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Platelets [38] (non-native to the dermis) | - Platelets are anucleate cytoplasmic discs derived from megakaryocytes that circulate in the blood and have major roles in hemostasis, thrombosis, inflammation, and vascular biology.
- Morphologically they have a discoid form and a diameter of 2-3 µm. Their normal count in humans is 150,000-400,000/µL, with a lifespan of 9-10 days
- Function: Normally, platelets circulate in the blood but upon endothelial injury or exposure to ECM contents, platelets adhere to the vascular lesion, recruit additional platelets and initiate a coagulation cascade.
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