Upward bound: follicular stem cell fate decisions.

Recent data suggest that heterogeneous compartments of the bulge display differential gene expression, and supply cells to different lineages within the pilosebaceous unit (Jaks et al, 2008; Jensen et al, 2009; Snippert et al, 2010). In particular, Lgr6 and Lrig1 are expressed above the CD34þ bulge region and Lgr6 expressing cells contribute primarily to the sebaceous gland (Figure 1). Thus, if and how the multipotent bulge cells give rise to cells to the sebaceous gland is not well understood. In this issue of The EMBO Journal, Petersson et al (2011) investigate how bulge cells contribute to the sebaceous gland in vivo using careful lineage tracing experiments and live bulge cell imaging in intact organ cultures. Defining the niche for stem cells and the mechanisms that control their activity and lineage pathways is essential for the use of these cells for tissue regeneration and disease prevention. In the skin, the stem cells of the hair follicle have the capacity to generate multiple lineages of the skin including the epidermis, hair follicle and sebaceous gland during grafting and wound healing. Genetic lineage tracing experiments (Morris et al, 2004; Zhang et al, 2009) have revealed that during skin homoeostasis, the activity of bulge cells is restricted to the lineages of the hair follicle and sebaceous gland, which compose the pilosebaceous unit. By crossing a mouse line expressing a tamoxifen inducible cre recombinase under the bulge-specific keratin 15 (K15) promoter (Morris et al, 2004) with reporter mouse lines, the authors are able to follow the contribution of bulge cell progeny towards the sebaceous gland. The sebaceous gland requires continual replacement of differentiated sebocytes, which lyse to release their specialized lipids into the hair canal for skin moisturization and protection. Sebaceous gland progenitor cells were identified that can contribute to the gland based on their expression of the transcription factor Blimp1 (Horsley et al, 2006), but the precise relationship between the bulge cells and sebaceous gland lineage cells had not been defined. Careful analysis of gene expression and the time course analysis of bulge cell progeny’s upwards migration from the quintessential CD34 region of the bulge allowed the authors to follow the progression of bulge cells through multiple regions of the follicle as they exit the stem cell niche. To visualize the lineage pathway of bulge cells in real time, the authors pioneered a live cell imaging technique in which labelled bulge cells were followed in real time in epidermal whole-mount preparations of tail skin using confocal microscopy. Cell division of bulge cells and migration of individual labelled progeny towards the upper isthmus were observed. Furthermore, this technique revealed the proliferation and migration of bulge cell progeny within the sebaceous gland. Taken together with the analysis of gene expression of labelled bulge cell progenitors, these data demonstrate that progeny of slow cycling bulge cells migrate above the hair follicle and follow a progression into the Lrg6 , Lrig1 upper bulge region to the Blimp1 progenitor population and into the sebaceous gland to repopulate the mature sebocytes.