Many adult regenerative cells divide infrequently but have high proliferative capacity. We developed a strategy to fluorescently label slow-cycling cells in a cell type-specific fashion. We used this method to purify the label-retaining cells (LRCs) that mark the skin stem cell (SC) niche. We found that these cells rarely divide within their niche but change properties abruptly when stimulated to exit. We determined their transcriptional profile, which, when compared to progeny and other SCs, defines the niche. Many of the >100 messenger RNAs preferentially expressed in the niche encode surface receptors and secreted proteins, enabling LRCs to signal and respond to their environment.Epidermis and its appendages undergo continuous renewal and maintain reservoirs of multipotent SCs whose descendants are organized spatially and temporally. The epidermal basal layer (BL) contains putative SCs in addition to the transiently amplifying (TA) cells, which give rise to terminally differentiating suprabasal layers (1-3). The BL and the hair follicle outer root sheath (ORS) are contiguous and biochemically similar ( fig. S1A). In the hair bulb, the dermal papilla (DP) maintains contact with matrix TA cells until they differentiate to form the inner root sheath (IRS) and hair shaft. Follicles periodically undergo cycles of growth (anagen), destruction (catagen), and rest (telogen). The zone between noncycling and cycling segments is a SC niche, the ORS "bulge" (4,5).Multipotent epithelial SCs with high proliferative potential reside in the bulge (6,7). The bulge contains the majority of infrequently cycling, label-retaining cells (LRCs), which can respond to anagen DP signals to regenerate the follicle. After wounding or transplantation, bulge cells give rise to epidermis, follicles, and sebaceous glands. Additionally, when dissected from rat whiskers and cultured, bulge cells yield more colonies than other follicle segments (7). It is not known what features define this specialized SC niche, what its interactions with bulgeLRCs are, and whether all LRCs are SCs. To begin to address these issues, we devised a strategy based on the prediction that bulge SCs are uniquely both slow-cycling and active for a keratinocyte-specific promoter. With this strategy, we purify and characterize bulge LRCs and related keratinocyte progeny in the BL and ORS. Analyses of their transcriptional profiles reveal the skin LRC mRNAs; some of these mRNAs are found in SCs of other tissues, whereas others specify the unique environment of the skin SC niche.To mark infrequently cycling cells of adult skin epithelium, we engineered transgenic mice to express histone H2B-green fluorescent protein (GFP) (8) controlled by a tetracyclineresponsive regulatory element (TRE). A tightly regulated TRE-mCMV-H2B-GFP founder animal was crossed with mice harboring a keratin 5 (K5) promoter-driven tet repressor-VP16

Epithelial-to-mesenchymal transition (EMT) is a process in which epithelial cells acquire mesenchymal features. In cancer, EMT is associated with tumor initiation, invasion, metastasis, and resistance to therapy. Recently, it has been demonstrated that EMT is not a binary process but occurs through distinct cellular states. Here, we review the recent studies that demonstrate the existence of these different EMT states in cancer and the mechanisms regulating their functions. We discuss the different functional characteristics such as proliferation, propagation, plasticity, invasion and metastasis associated with the distinct EMT states. We summarize the role of the transcriptional and epigenetic landscapes, gene regulatory network and their surrounding niche in controlling the transition trough the different EMT states.

Natural peptides displaying agonist activity on the orphan G protein-coupled receptor GPR54 were isolated from human placenta. These 54-, 14,-and 13-amino acid peptides, with a common RF-amide C terminus, derive from the product of KiSS-1, a metastasis suppressor gene for melanoma cells, and were therefore designated kisspeptins. They bound with low nanomolar affinities to rat and human GPR54 expressed in Chinese hamster ovary K1 cells and stimulated PIP 2 hydrolysis, Ca 2؉ mobilization, arachidonic acid release, ERK1/2 and p38 MAP kinase phosphorylation, and stress fiber formation but inhibited cell proliferation. Human GPR54 was highly expressed in placenta, pituitary, pancreas, and spinal cord, suggesting a role in the regulation of endocrine function. Stimulation of oxytocin secretion after kisspeptin administration to rats confirmed this hypothesis.