Skeletal Research Center, Biology Department, Case Western Reserve University, Cleveland, OH 44106, USA
* Author for correspondence (e-mail: jms30{at}cwru.edu)
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Summary |
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Key words: Skin, Fibroblasts, Skin equivalents
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Introduction |
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Papillary and reticular dermal fibroblasts |
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Mechanical separation of skin (dermatoming) into defined papillary and reticular layers allows establishment of explant cultures of cells from each layer. Papillary fibroblasts divide at faster rates than do site-matched reticular fibroblasts (Harper and Grove, 1979; Azzerone and Macieira-Coelho, 1982; Schafer et al., 1985
; Sorrell et al., 1996
; Sorrell et al., 2004
). Reticular dermal fibroblasts seeded into type I collagen lattices contract them faster than do papillary dermal fibroblasts (Schafer et al., 1985
; Sorrell et al., 1996
). When grown to confluence in monolayer culture, the papillary cells attain a higher cell density partly because they are not fully contact inhibited (Schafer et al., 1985
; Sorrell et al., 2004
).
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Extracellular matrix differences |
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Experimental studies have explored the issue of whether cultured papillary and reticular fibroblasts produce different amounts and types of extracellular matrix molecule that might account for the observed differences in skin (Table 2). In monolayer cultures, Schönherr et al. found that papillary dermal fibroblasts secrete significantly more decorin than did corresponding reticular cells, and papillary fibroblasts contain more decorin mRNA (Schönherr et al., 1993). By contrast, the two cellular populations produce identical amounts of biglycan. Another study found that site-matched papillary and reticular fibroblasts differ in the relative levels of the proteoglycans decorin and versican that they produce (Sorrell et al., 1999b
).
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Akagi et al. found that fibroblasts derived from the upper, middle and lower thirds of the dermis produced significantly different amounts of mRNA for the 1(XVI) of type XVI collagen (Akagi et al., 1999
). By contrast, Tajima and Pinnell quantified the amounts of type I and type III collagens produced by monolayer cultures to see whether synthetic differences might account for the observed in vivo differences (Tajima and Pinnell, 1981
). They found no differences in the production of type I and type III collagens by these two populations of cultured cells, although they noted an elevated amount of type I procollagen in the medium of papillary fibroblast cultures. Thus, cultured papillary and reticular fibroblasts exhibit stable differences in the production of some, but not all, extracellular matrix molecules.
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Fibroblasts and basement membrane formation |
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Coculture of fibroblasts and keratinocytes modifies the activities of both cell types. Keratinocytes induce the expression of transforming growth factor (TGF)-ß2 by dermal fibroblasts (Smola et al., 1994). Fibroblasts regulate the production of laminins and type VII collagen by keratinocytes, possibly through TGF-ß signaling (König and Bruckner-Tuderman, 1991
; König and Bruckner-Tuderman, 1994
; Monical and Kefalides, 1994
). The kinetics of basement membrane formation has also been studied in organotypic coculture models in which fibroblasts were either present or omitted (Smola et al., 1998
). Specific basement membrane components gradually appeared at the DEJ; however, the kinetics varied, depending on whether fibroblasts were present. The production of type IV collagen, laminin-1 and type VII collagen by keratinocytes cultured alone was significantly delayed or absent, suggesting that fibroblasts influenced the production of these matrix molecules. On the dermal side, the steady-state mRNA levels of type IV collagen
1 message in fibroblasts were significantly enhanced when keratinocytes were present. Together, these studies indicate that elements of basement membrane production are co-regulated by fibroblasts and keratinocytes.
Not all dermal fibroblasts interact equally well with keratinocytes in the formation of a basement membrane. Moulin et al. showed that myofibroblasts obtained from wound sites do not support keratinocyte differentiation and basement membrane formation to the same extent as do normal dermal fibroblasts (Moulin et al., 2000). Consequently, the ability was compared of site-matched papillary and reticular dermal fibroblasts to support basement membrane formation (Sorrell et al., 2004
). Papillary dermal fibroblasts appeared to induce basement membrane formation faster when reticular fibroblasts were present. Therefore, fibroblasts adjacent to the epidermis might either produce more extracellular matrix components of the basement membrane and/or produce soluble factors that influence keratinocytes to re-establish a basement membrane.
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Intercellular communication and interfollicular dermal fibroblasts |
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Fibroblasts release growth factors/cytokines that play a significant role in wound repair by modulating the activity of keratinocytes. Smola et al. found that coculture of fibroblasts and keratinocytes results in increased levels of KGF-1, IL-6 and GM-CSF mRNAs (Smola et al., 1993). The level of KGF-1 mRNA and the amount of protein released into culture medium by cultured dermal fibroblasts were upregulated by treatment of these cells with IL-1 (Brauchle et al., 1994
; Chedid et al., 1994
; Maas-Szabowski and Fusenig, 1996
). KGF-1 in turn enhanced the release of IL-1
by keratinocytes. Thus, a paracrine loop is established in situations where dermal fibroblasts and keratinocytes coexist (Maas-Szabowski et al., 1999
).
Soluble factors released by fibroblasts do not possess inductive characteristics with respect to interfollicular keratinocytes. Nonetheless, these factors can modulate specific aspects of epidermal formation. Overexpression of KGF-1 results in a hyperproliferative epidermis. This might result from enhanced proliferation of basal keratinocytes and suppression of terminal differentiation (Guo et al., 1993; Hines and Allen-Hoffmann, 1996
; Szabowski et al., 2000
; Andreadis et al., 2001
). Excessive KGF-1 might also induce flattening of the basal surface of the epidermis (Andreadis et al., 2001
). By contrast, overexpression of GM-CSF results in increased apoptosis of cultured keratinocytes, and overexpression of KGF-2 could accelerate keratinocyte differentiation (Breuhahn et al., 2000
; Suzuki et al., 2000
; Marchese et al., 2001
). These observations have led to the proposal that the epidermal response to fibroblast-derived signaling molecules depends upon the ratio of these factors. Fusenig and coworkers have proposed that the ratio of KGF-1 to GM-CSF presented to epidermal cells determines the status of this tissue (Maas-Szabowski et al., 2001
). Site-matched papillary and reticular dermal fibroblasts differ significantly in the release of KGF-1 and GM-CSF into culture medium. Typically, the ratio of GM-CSF to KGF-1 is higher in papillary fibroblasts than in corresponding reticular cells (Sorrell et al., 2004
). Thus, these two populations of cells exert subtle differences on epidermal proliferation and differentiation.
Communication between fibroblasts and keratinocytes appears to involve AP-1 target genes in dermal fibroblasts. Szabowski et al. examined fibroblasts from Jun-knockout and JunB-knockout mouse embryos and found that the Jun-/- cells produce very low levels of KGF-1 and GM-CSF, whereas JunB-/- cells produce elevated levels of these factors (Szabowski et al., 2000). Incorporation of these fibroblasts into bi-layered skin equivalents with normal adult human keratinocytes for the epidermal layer led to strikingly different results. Epidermal layers on skin equivalents containing Jun-/- fibroblasts were atrophic, basal cell proliferation was reduced, and terminal differentiation was delayed. JunB-/- fibroblasts caused epidermal hyperplasia. IL-1 and other inflammatory factors, such as tumor necrosis factor (TNF)-
, activate AP-1-mediated transcription and enhance the activity of NF-
B (Angel and Szabowski, 2002
). Differences in the phenotypes of fibroblasts in skin might be related to how these cells respond to external signals and modulate the diverse group of genes regulated by AP-1 transcription factors.
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Dermal fibroblastic cells are associated with hair follicles |
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The fibroblast in cutaneous wound repair |
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Myofibroblasts, in response to monocyte/macrophage-derived factors, produce a provisional wound matrix that is enriched in fetal-like fibronectin and hyaluronan (Clark, 1990; Gailit and Clark, 1994
; Juhlin, 1997
; Singer and Clark, 1999
). These cells also provide the motive force to contract the wound (Sappino et al., 1990
). Myofibroblasts disappear from the wound site, apparently by apoptosis, and are replaced by a second wave of fibroblasts that initiate the formation of a collagenous matrix (Grinnell et al., 1999
). However, their ability to organize it is impaired, which results in the formation of scar tissue (Gailit and Clark, 1994
; Shah et al., 1994
; Shah et al., 1995
; Singer and Clark, 1999
). Fetal skin is repaired without scar formation (Adzick and Lorenz, 1994
; Armstrong and Ferguson, 1995
; Liechty et al., 2000
). This is mainly owing to differences in fetal and adult fibroblast phenotypes (Schor et al., 1985
; Olsen and Uitto, 1989
; Cullen et al., 1997
; Gosiewska et al., 2001
). The low level of growth factors/cytokine production by fetal cells, especially TGF-ß1, appears to be a major factor in the absence of scar formation (Shah et al., 1994
; Shah et al., 1995
; Eckes et al., 2000
). The aberrant fibroblast phenotype also appears to contribute to fibrotic disorders, such as keloid formation and scleroderma (Garner et al., 1993
; Ghahary et al., 1994
; Ghahary et al., 1996
; Sollberg et al., 1994
; Kirk et al., 1995
; Nakaoka et al., 1995
; Herrick et al., 1996
; Hasan et al., 1997
; Agren et al., 1999
). Signals such as TGF-ß and connective tissue growth factor play a significant role in the latter process (Grotendorst, 1997
).
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The dermal fibroblast in bioengineering |
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Dermal and skin equivalents as biological models |
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Michel et al. have investigated skin equivalents as potential tools for percutaneous absorption (Michel et al., 1993). They prepared human skin equivalents such that a constant surface area was present and found that absorption of chemical agents depends on the thickness of the epidermis and its stratum corneum. This process was not entirely equivalent to that observed in mice, but was sufficient to suggest that it might be used as an effective model for pharmacological and cosmetic testing. Development of skin equivalents that contain other types of cell, such as immunocompetent cells and vascular endothelial cells (Regnier et al., 1997
; Guironnet et al., 2001
; Ponec, 2002
; Supp et al., 2002
), might also provide insight into biological and pharmacological responses.
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Dermal and skin equivalents for skin replacement |
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Concluding remarks |
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Fibroblast diversity in the skin raises questions that will require experiments to provide answers. Inductive influences from the epidermis result in the differentiation of fibroblasts associated with hair follicles. However, the factor(s) or event(s) that drives the differentiation of papillary and reticular cells are unknown. Furthermore, our knowledge of the physiological characteristics that differentiate papillary from reticular fibroblasts remains limited. Additional information in this regard will expand our conceptualization of the function of fibroblasts in skin. There is currently limited information that suggests that AP-1 and homeobox genes and their regulators play roles in determining fibroblast diversity. Additional studies are required to define the roles of these and possibly other regulatory genes in establishing and maintaining fibroblast diversity. With the increased reliance on the development and application of three-dimensional skin equivalents for biological and clinical purposes, it will be necessary to be more selective about the choice of fibroblast to be employed.
Finally, the term `dermal fibroblast' is an oversimplification. In reality, dermal fibroblasts are a dynamic, diverse population of cells. This means that we should take greater care defining the population of dermal fibroblast that is used in experimental studies. We are only beginning to understand the function of these cells in defining the structure and organization of skin and their complex intercellular interactions. Our current knowledge of fibroblast physiology is largely based upon monolayer culture studies. These studies more closely reflect the status of these cells in an early wound repair situation. The use of three-dimensional dermal and skin equivalents in future studies should provide more relevant information regarding possible physiological differences between fibroblast subpopulations in vivo. Much work will be required in the future if we are to understand and appreciate fully this diverse population of cells.
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Acknowledgments |
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