Exp Dermatol 1999: 8: 80–88 Copyright C Munksgaard 1999 Printed in Denmark ¡ All rights reserved ISSN 0906-6705 Controversies in Experimental Dermatology Section Editor: Ralf Paus, Berlin Epithelial stem cells in the skin: definition, markers, localization and functions Cotsarelis G, Kaur P, Dhouailly D, Hengge U, Bickenbach J. Epithelial G. Cotsarelis, P. Kaur, stem cells in the skin: definition, markers, localization and functions. D. Dhouailly, U. Hengge Exp Dermatol 1999: 8: 80–88. C Munksgaard, 1999 and J. Bickenbach Key words: keratinocytes – epidermis – hair follicle – bulge – transit amplifying cells – b 1 integrin, a 6 integrin – gene therapy In recent years, cutaneous epithelial stem cells have attained a genuine celebrity status. They are con- sidered the key resource for epidermal and skin ap- pendage regeneration, and are proposed as a prefer- ential target of cutaneous gene therapy. Follicular epithelial stem cells may also give rise to a large variety of epithelial tumors, and cutaneous epithelial stem cells likely are crucial targets for physical or chemical agents (including carcinogens) that damage the skin and its appendages. However, as this Con- troversies feature illustrates, few experts can agree on how exactly to define and identify these elusive Viewpoint 1 What is a stem cell? In the context of a rapidly proliferating tissue such as the cutaneous epithelium, a stem cell can be de- fined as a relatively undifferentiated, multipotent, generally quiescent cell with a high proliferative potential that gives rise to both other stem cells and more proliferative transit amplifying (TA) cells. TA cells are responsible for the immediate replenishment of cells that are lost to the environ- ment after terminal differentiation. Other stem cell attributes include the ability to proliferate in re- sponse to wounding and hyperproliferative stimuli, high b 1 integrin expression and a life span which exceeds that of the organism (for reviews, see (1, 2)). Although enough evidence exists to support 80 cells, or on where precisely in the skin they are local- ized. Given their potential importance in skin bi- ology, pathology and future dermatological therapy, it is, therefore, timely to carefully reconsider the basic questions: What exactly is a stem cell, and how can we reliably identify epithelial stem cells? How many different kinds are there, and how do they dif- fer functionally? Where exactly in the skin epithel- ium is each of the putative stem cell subpopulations located, and can we selectively manipulate any of them? the concept that the epidermis is organized into a hierarchy of stem, TA and terminally differentiated cells, in hair-bearing skin hair follicle bulge kera- tinocytes best satisfy the wide array of stem cell criteria (see Table 1). This suggests that, under physiological conditions, the hair follicle bulge serves as the ultimate reserve of both epidermal and hair follicle keratinocytes. How are stem cells identified? In vivo detection of slowly-cycling cells The two most salient features of stem cells, namely their slowly-cycling nature and high proliferative potential, can be identified by in vivo and in vitro