J. Soc. Cosmet. Chem., 22, 109-118 (Feb. 4, 1971) Transplantation of Skin to Unnatural Sites as a Means of Studying Its Regional Differences R. E. BILLINGHAM, Ph. D3 Presented May 26-27, 1970, New York City Synopsis--HETEROTOPIC and other SKIN GRAFTING experiments, carried out on adult laboratory RODENTS, indicate that the germinal cells in the basal layer of many struc- rurally and functionally distinctive types of epidermis are equipotential. Their characteris- tic D1FFERENTIATIVE BEHAVIOR is determined by interaction with the particular type of dermis that forms their normal substrate. However, there are some exceptions which include the epidermis of tongue, cornea, esophagus, and hamster's cheek pouch, whose specificities are intrinsically maintained. They conserve their original specificity even when caused to grow on anatomically unnatural types of mesenchymal tissue bed. INTRODUCTION One of the central problems in the biology of skin is to account for the origin and maintenance throughout life of the tremendous variety of structural and functional diversity displayed by epidermis (1, 2). There are many different kinds of superficial epidermis, ranging from the ex- quisitely transparent, highly sensitive epidermis of the cornea, to the thick, tough, and relatively insensitive epidermis of the sole of foot. In addition, there is a fantastic range of epidermal appendages which in- clude hairs of functionally and anatomically different types, nails and claws, and hard scales. Finally, there is a multiplicity of types of func- * Some of the work described in this article was supported by U. S. Public Health Service Grant AI 07001. ? Department of Medical Genetics, University of Pennsylvania, School of Medicine, Phila- delphia, Pa. 19104. 109

110 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS tionally important glands of epidermal origin, including sebaceous, sweat, cerumen, mammary, and scent glands such as the preputial glands of the musk deer familiar to the perruiner. As Grobstein (3) has pointed out, one of the most important processes in embryonic development is the interaction or intercommunication be- tween cells and tissues of dil•erent ontogenetic origins and properties brought into association by so-called "morphogenetic movements." These "heterotypic" interactions are responsible for the emergence of a wide range ot• new types of differentiated cells and tissues. It is now gen- erally believed that the differentiae of the skin all result from heterotypic interactions between the epithelial and mesenchymal precursors of epi- dermis and dermis in embryonic development. However, at present we know little about the nature and modus operahall of the postulated medi- ators of these interactions apart from the fact that they are capable of diffusing across cell-impermeable Millipore filter membranes in tissue culture systems (4). In adult subjects we usually pay little attention to the connective tis- sue or derreal substrates upon which the various types of superficial epi- dermis rest and which closely and intimately invest all epidermal ap- pendages. Of course, the dermis is given credit for: (a) mediating essential metabolic exchanges between the avascular epidermis and the fine plexus of blood vessels in the underlying connective tissue, and (b) providing essential mechanical support for the lowermost layer of epi- dermal cells which are so firmly bonded to it. However, throughout the epidermal system wherever there is a continuous loss of cells which is con- stantly being made good by the proliferative activity of an underlying germinal layer of Malpighian cells, it is evident that "instructions" of some kind must indicate to the newly-formed cells which particular path- way of cytodifferentiation or specialization, at both the biochemical and structural levels, they must follow so as faithfully to maintain the type of epidermal structure of which they are part. Think how disastrous it would be if new cells in our corneal epidermis suddenly began to become opaque and loosely united to one another at the surface, like the cells on the surface of our bodies, or if the epidermis on the soles of our feet sud- denly became delicate like that of our lips or conjunctiva! There are two obvious, not necessarily mutually exclusive, possible explanations for the conservation of epidermal specificities throughout adult life (2): (a) There are intrinsic differences, of developmental ori- gin, between the basal layer or germinal cells of the different kinds of epidermis which enable them to "breed true" of their own accord,