Résumé
The skin epidermis and its appendages provide a protective barrier that is impermeable to harmful microbes and also prevents dehydration. To perform their functions while being confronted with the physico-chemical traumas of the environment, these tissues undergo continual rejuvenation through homeostasis and in addition, they must be primed to undergo wound-repair in response to injury. The skin’s fountain of youth for maintaining tissue homeostasis, regenerating hair and repairing the epidermis following injury is its stem cells, which reside in the adult hair follicle, sebaceous gland and epidermis. Stem cells have the remarkable capacity to both self-perpetuate and also give rise to the differentiating cells that constitute one or more tissues. In recent years, researchers have begun to uncover the properties of skin stem cells, and unravel the mysteries underlying their remarkable capacity to perform these feats.
The adult skin epithelium is composed of molecular building blocks, consisting of a pilosebaceous unit (HF and sebaceous gland) and its surrounding interfollicularepidermis (IFE) (Blanpain and Fuchs 2006). Both the IFE and the sebaceous gland contain their own progenitor cells for normal homeostasis in the absence of injury (Levy et al. 2005; Horsley et al. 2006; Levy et al. 2007). HFs contain a niche of relatively quiescent follicle stem cells that are normally activated at the start of each new hair cycle. Upon wounding, these cells are able to repair the epidermis and sebaceous glands. Like many other adult stem cells of the body, skin epithelial stem cells were predicted to be relatively infrequently utilized, and hence slow-cycling (Taylor et al. 2000; Oshima et al. 2001). Like other stratified squamous epithelia and many glandular epithelia, the skin epithelial cells with proliferative activity were known to express keratins 5 and 14 (Fuchs and Green 1980; Vassar et al. 1989). On the basis of these two characteristics, we devised a pulse-chase strategy with a fluorescent histone to identify and fluorescently mark the slow-cycling K5/K14-positive cells of mice (Tumbar et al. 2004). Located in a region of the hair follicle known as the bulge, special cells within this niche could be activated to proliferate and divide with each new hair cycle and could be mobilized to repair wounds to the epidermis. Using fluorescence activated cell sorting, cell culture, and skin engraftments with clonally derived progeny of single bulge cells, we showed that these cells are in fact stem cells, and they have multipotent capacity (Blanpain et al. 2004; Morris et al. 2004; Tumbar et al. 2004; Ito et al. 2005).
We’ve used transcriptional profiling and genetic analyses to understand how these stem cells maintain quiescence and become activated upon initiation of a new hair cycle. We’ve revealed roles for the Wnt signaling pathway in stem cell activation, self renewal, hair shaft production and tumorigenesis (Zhou et al. 1995; Gat et al. 1998; Chan et al. 1999; DasGupta and Fuchs 1999; Merrill et al. 2001; McLean et al. 2004; Lowry et al. 2005; Nguyen et al. 2006). We’ve revealed roles for the BMP pathway in controlling stem cell quiescence (Kobielak et al. 2003; Kobielak et al. 2007; Horsley et al. 2008). Collectively, the studies from my laboratory and others (Huelsken and Birchmeier 2001; Van Mater et al. 2003; Andl et al. 2004; Lo Celso et al. 2004; Ito et al. 2007) suggest a working model for stem cell quiescence, self-renewal and activation in the hair follicle during normal homeostasis and wound repair.
