Fibroblasts represent a diverse population of cells (Fries etal., 1994). Phenotypic differences are manifested in a varietyof ways: extracellular matrix production and organization, productionof growth factors/cytokines, and participations in inflammatoryresponses (Fries et al., 1994; Smith et al., 1997; Doane andBirk, 1991; Limeback et al., 1982; Derdak et al., 1992; Stephenset al., 2001). In the skin, two forms of fibroblast heterogeneityhave been noted. Intrasite heterogeneity relates to the positionof fibroblasts in the context of epidermal structures. Thus,papillary, reticular and hair-follicle-associated fibroblastsdiffer from each other. A second type of heterogeneity is basedupon the anatomical location within the body. Thus, interfollicularfibroblasts from scalp, face, trunk, leg, and so on exhibitsubtle differences from each other. Less is currently knownabout these intersite differences in fibroblasts. Chang et al.have shown that human dermal fibroblasts obtained from variousanatomical sites express different homeobox transcription factors(Chang et al., 2002). The AP-1 family of transcription factorsis important in regulating the production of factors that regulateepithelial-mesenchymal interactions, cellular proliferationand extracellular matrix production (Angel and Szabowski, 2002;Shaulian and Karin, 2002). Papillary and reticular dermal fibroblastsdiffer in these characteristics. Therefore, additional studiesrelated to this family of factors might help us to understandthe differences between subpopulations of dermal fibroblasts.
Fibroblast diversity in the skin raises questions that willrequire experiments to provide answers. Inductive influencesfrom the epidermis result in the differentiation of fibroblastsassociated with hair follicles. However, the factor(s) or event(s)that drives the differentiation of papillary and reticular cellsare unknown. Furthermore, our knowledge of the physiologicalcharacteristics that differentiate papillary from reticularfibroblasts remains limited. Additional information in thisregard will expand our conceptualization of the function offibroblasts in skin. There is currently limited informationthat suggests that AP-1 and homeobox genes and their regulatorsplay roles in determining fibroblast diversity. Additional studiesare required to define the roles of these and possibly otherregulatory genes in establishing and maintaining fibroblastdiversity. With the increased reliance on the development andapplication of three-dimensional skin equivalents for biologicaland clinical purposes, it will be necessary to be more selectiveabout the choice of fibroblast to be employed.
Finally, the term `dermal fibroblast' is an oversimplification.In reality, dermal fibroblasts are a dynamic, diverse populationof cells. This means that we should take greater care definingthe population of dermal fibroblast that is used in experimentalstudies. We are only beginning to understand the function ofthese cells in defining the structure and organization of skinand their complex intercellular interactions. Our current knowledgeof fibroblast physiology is largely based upon monolayer culturestudies. These studies more closely reflect the status of thesecells in an early wound repair situation. The use of three-dimensionaldermal and skin equivalents in future studies should providemore relevant information regarding possible physiological differencesbetween fibroblast subpopulations in vivo. Much work will berequired in the future if we are to understand and appreciatefully this diverse population of cells.