Characterisation of hair follicle stem cell function in epidermal regeneration and tumourigenesis

Mammalian epidermis is a highly dynamic epithelium comprising the interfollicular epidermis, hair follicles (HF) and associated sebaceous glands (SG). Spontaneous regeneration and cellular turn over of each of these compartments is maintained by multiple stem cell (SC) and progenitor populations (Cotsarelis, 2006; Fuchs and Horsley, 2008). Although there are implications that different SC/progenitors participate in SG regeneration, the cellular process of SG maintainance still needs to be uncovered (Blanpain and Fuchs, 2009). For instance, it is unknown whether different SC/progenitor reservoirs act autonomously or are interconnected and arranged within a certain hierarchy (Jaks et al, 2010). To investigate potential functions and epidermal contribution of SC from the HF bulge, we have developed an inducible Cre-mouse model enabling us to track the fate of single HFSC-derived progeny. From these lineage tracing experiments we have learned that HFSC-derived progenitors are not only essential for cyclic HF regeneration but also continuously reconstitute the SG. During this process of SG renewal, cells exit the HF bulge and transit through distinct epidermal progenitor compartments before finally repopulating the SG. Thus, our data imply a hierarchy of multipotent keratinocytes underlying epidermal homeostasis. Furthermore, tracking HFSC-derived progeny in long term studies revealed that the SC pool itself is replenished probably by symmetric cell division. Therefore, different signaling cues must exist to instruct HFSC to regenerate different integral parts of the epidermis or to replenish the SC pool. By forcing basal keratinocytes into the sebocyte lineage through manipulation of Lef1 (Niemann et al., 2002), one of the crucial regulators of fate decision, we could identify HFSC as cells of origin for development of ectopic SG. Additionally, new sebocyte progenitor compartments are established adjacent to de novo formed SG. Intriguingly, fate mapping experiments within an inducible skin tumour model (Niemann et al., 2007) clearly demonstrated that HFSC-derived progeny contributes to sebaceous tumourigenesis. Finally, manipulation of Lef1 signalling within the HFSC niche in a transgenic mouse model results in formation of sebaceous adenoma, supporting the hypothesis that HFSC indeed are targeted by transformational events during skin tumour development