Epithelial stem cells in the skin: definition, markers, localization and functions

Abstract

Key words: keratinocytes -epidermis -hair follicle -bulge -transit amplifying cells -b 1 integrin, a 6 integrin -gene therapyIn recent years, cutaneous epithelial stem cells have attained a genuine celebrity status. They are considered the key resource for epidermal and skin appendage regeneration, and are proposed as a preferential 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 Controversies feature illustrates, few experts can agree on how exactly to define and identify these elusive Viewpoint 1What is a stem cell?In the context of a rapidly proliferating tissue such as the cutaneous epithelium, a stem cell can be defined 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 environment after terminal differentiation. Other stem cell attributes include the ability to proliferate in response 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 localized. Given their potential importance in skin biology, 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 differ functionally? Where exactly in the skin epithelium is each of the putative stem cell subpopulations located, and can we selectively manipulate any of them?

Partial enrichment of a population of human limbal epithelial cells with putative stem cell properties based on collagen type IV adhesiveness

“…These include: (1) slow cycling or long cell cycle time during homeostasis in vivo; (2) small size with poor differentiation and primitive cytoplasm; (3) high proliferative potential after wounding or placement in culture; and (4) the ability for self-renewal and functional tissue regeneration (see review articles by Blau et al, 2001;Cotsarelis et al, 1999;Lavker and Sun, 2000;Watt, 2000;Watt and Hogan, 2000). The cell population selected by rapid adhesion to collagen IV possesses several of these properties, including enriched slow-cycling cells identified by BrdU LRCs, less expression of differentiation markers with higher levels of molecular markers that have been identified in the basal limbal epithelium, and high proliferative capacity in culture.…”

Transdifferentiation of corneal epithelium: evidence for a linkage between the segregation of epidermal stem cells and the induction of hair follicles during embryogenesis.

“…This would imply a greater degree of plasticity in these cells than has hitherto been recognised. In the interfollicular epidermis this is difficult to determine as there appear to be secondary stem cells dispersed and intermingled with the transient cells throughout the basal layer of the epidermis (reviewed in Cotsarelis et al, 1999;Watt, 2001;Fuchs and Raghavan, 2002). The primary source of stem cells in the epidermis rests in the bulge region of the hair follicle (Taylor et al, 2000;Merrill et al, 2001;Oshima et al, 2001).…”

Tissue-specific expression and long-term deposition of human collagen VII in the skin of transgenic mice: implications for gene therapy

“…41 Indeed, positive identification of keratinocyte stem cells and their stable transduction with genes for structural proteins would be optimal for gene therapy for a number of genodermatoses. [42][43][44] A prerequisite for demonstration of utility of the human COL7A1 gene vector for therapy is that appropriate tissue pattern of expression can be recapitulated in the transgenic animal. Our study shows for the first time that the human COL7A1 gene can be successfully expressed in the skin of transgenic mice and that the collagen VII protein, that is synthesized and processed appropriately, is stable and present continually along the basement membrane zone in detectable amounts 19 months after birth.…”