Our previous studies of the development of both normal and abnormal human skin have documented changes in the expression of various differentiation-specific markers coordinate with the morphology of the tissue. This work has provided a coherent picture of cutaneous development and identified events and periods of development which are presumed to be critical in establishing the template of the normal, adult skin. We are now placing more emphasis in our studies on understanding the kinds of cellular interactions that occur to effect the changes described and will address the role of cell-cell and tissue interactions in modulating niorphogenesis and differentiation of the skin. These kinds of interactions are best exemplified in the formation of epidermal appendages, hence the focus of this proposal on the formation of pilosebaceous structures. We are using a very well characterized system that can be studied directly in vivo (fresh tissue) and experimentally in vitro (cell culture, organ culture, grafting). We have developed the suspension organ culture which supports, reproducibly, the formation and continued development of epidermal appendages (see preliminary data and appendix) for as long as 60 days and maintains, and permits growth, of epidermis and dermis in an apparently normal manner. We are unaware of any other human skin culture system which has this potential. This culture system will be used to identify the requirements for the induction, initiation, growth, differentiation and maintenance of epidermal appendages in developing human skin, and to determine the presumptive roles of epithelial (keratinocytes) and mesenchymal cells in the interaction. We will focus on parts played by growth factors (NGF, EGF, POGF, TGF-8) and their receptors (some of which specifically influence epithelial cells, others which are specific for mesenchymal cells), matrix components (collagen types 1, 111, V and VI; fibronectin and collagenase), other relevant molecules (e.g., minoxidil) and nerve fibers in hair follicle development. Skin from patients affected with X-linked hypohidrotic ectodermal dysplasia, a genetic disorder in which development and postnatal abnormalities of appendage formation are the hallmark of the diseases, will be studied in order to determine whether any of the growth factors, etc. identified to be important in the ontogeny of appendages are abnormally expressed in the adult tissue.
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