In the age of stem cell engineering it is critical to understand how stem cell activity is regulated during regeneration. Hairs are miniorgans that undergo cyclic regeneration throughout adult life 1 , and are an important model for organ regeneration. Hair stem cells located in the follicle bulge 2 are regulated by the surrounding microenvironment, or niche 3 . The activation of such stem cells is cyclic, involving periodic b-catenin activity [4][5][6][7] . In the adult mouse, regeneration occurs in waves in a follicle population, implying coordination among adjacent follicles and the extrafollicular environment. Here we show that unexpected periodic expression of bone morphogenetic protein 2 (Bmp2) and Bmp4 in the dermis regulates this process. This BMP cycle is out of phase with the WNT/b-catenin cycle, thus dividing the conventional telogen into new functional phases: one refractory and the other competent for hair regeneration, characterized by high and low BMP signalling, respectively. Overexpression of noggin, a BMP antagonist, in mouse skin resulted in a markedly shortened refractory phase and faster propagation of the regenerative wave. Transplantation of skin from this mutant onto a wild-type host showed that follicles in donor and host can affect their cycling behaviours mutually, with the outcome depending on the equilibrium of BMP activity in the dermis. Administration of BMP4 protein caused the competent region to become refractory. These results show that BMPs may be the long-sought 'chalone' inhibitors of hair growth postulated by classical experiments. Taken together, results presented in this study provide an example of hierarchical regulation of local organ stem cell homeostasis by the inter-organ macroenvironment. The expression of Bmp2 in subcutaneous adipocytes indicates physiological integration between these two thermoregulatory organs. Our findings have practical importance for studies using mouse skin as a model for carcinogenesis, intracutaneous drug delivery and stem cell engineering studies, because they highlight the acute need to differentiate supportive versus inhibitory regions in the host skin.Mammalian skin contains thousands of hair follicles, each undergoing continuous regenerative cycling. A hair follicle cycles through anagen (growth), catagen (involution) and telogen (resting) phases, and then re-enters the anagen phase. At the base of this cycle is the ability of hair follicle stem cells to briefly exit their quiescent status to generate transient amplifying progeny, but maintain a cluster of stem cells. It is generally believed that a niche microenvironment is important in the control of stem cell homeostasis in various systems 8 . Within a single hair follicle, periodic activation of b-catenin in bulge stem cells is responsible for their cyclic activity 3 . However, how these stem cell activation events are coordinated among neighbouring hairs remains unclear. It is possible that a population of hair follicles could cycle simultaneously, randomly or in coordinated waves...

Stem cells cycle through active and quiescent states. Large populations of stem cells in an organ may cycle randomly or in a coordinated manner. Although stem cell cycling within single hair follicles has been studied, less is known about regenerative behavior in a hair follicle population. By combining predictive mathematical modeling with in vivo studies in mice and rabbits, we show that a follicle progresses through cycling stages by continuous integration of inputs from intrinsic follicular and extrinsic environmental signals based on universal patterning principles. Signaling from the WNT/bone morphogenetic protein activator/inhibitor pair is coopted to mediate interactions among follicles in the population. This regenerative strategy is robust and versatile because relative activator/inhibitor strengths can be modulated easily, adapting the organism to different physiological and evolutionary needs.

Regenerative cycling of hair follicles offers an unique opportunity to explore the role of circadian clock in physiological tissue regeneration. We focused on the role of circadian clock in actively proliferating transient amplifying cells, as opposed to quiescent stem cells. We identified two key sites of peripheral circadian clock activity specific to regenerating anagen hair follicles, namely epithelial matrix and mesenchymal dermal papilla. We showed that peripheral circadian clock in epithelial matrix cells generates prominent daily mitotic rhythm. As a consequence of this mitotic rhythmicity, hairs grow faster in the morning than in the evening. Because cells are the most susceptible to DNA damage during mitosis, this cycle leads to a remarkable time-of-day-dependent sensitivity of growing hair follicles to genotoxic stress. Same doses of γ-radiation caused dramatic hair loss in wild-type mice when administered in the morning, during mitotic peak, compared with the evening, when hair loss is minimal. This diurnal radioprotective effect becomes lost in circadian mutants, consistent with asynchronous mitoses in their hair follicles. Clock coordinates cell cycle progression with genotoxic stress responses by synchronizing Cdc2/Cyclin B-mediated G 2 /M checkpoint. Our results uncover diurnal mitotic gating as the essential protective mechanism in highly proliferative hair follicles and offer strategies for minimizing or maximizing cytotoxicity of radiation therapies.proliferation | radiation therapy | hair cycle M any biological events are rhythmic at different levels of organization, from cellular to behavioral. Diverse clock mechanisms have evolved to endow such rhythmic events with proper periodicity. The circadian clock helps organisms anticipate predictable daily changes in their environment and to prepare for diurnal and seasonal adaptations. Mechanistically, the circadian clock is based on the autoregulatory gene expression feedback loop in its core consisting of Clock/brain and muscle ARNT-like 1 (Bmal1)/neuronal PAS domain-containing protein 2 transcription factors that induce Period (Per)/Cryptochrome (Cry) genes expression, the protein products of which, in turn, inhibit these factors (1). Through its output mechanisms, the circadian clock generates daily fluctuations in various homeostatic processes (2). In mammals, a "master circadian clock" in the suprachiasmatic nucleus (SCN) uses both direct and indirect mechanisms to generate daily rhythms in several systemic signaling factors. In the peripheral tissues, local circadian clock also orchestrates intrinsic rhythms for their respective functions.We wanted to examine the role of circadian rhythms in hair cycle, which is a complex regenerative process consisting of sequential phases of hair production (anagen), followed by hair follicle inactivity (telogen). The timing of anagen initiation and anagen cessation (also known as catagen) largely determine the length of this cycle. Following anagen initiation, proliferation of epithelial cells and termin...

Epithelial appendages , such as mammary glands and hair , arise as a result of epithelial-mesenchymal interactions. Bone morphogenetic proteins (BMPs) are important for hair follicle morphogenesis and cycling and are known to regulate a wide variety of developmental processes. For example , overexpression of BMPs inhibits hair follicle formation. We hypothesized that the down-regulation of the BMP signaling pathway in the basal epidermis expands regions that are competent to form hair follicles and could alter the fate of the epithelium in the mouse nipple to a hair-covered epidermal phenotype. To test our hypothesis , we used a transgenic mouse model in which keratin 14 (KRT14) promoter-mediated overexpression of Noggin , a BMP antagonist , modulates BMP activity. We observed the conversion of nipple epithelium into pilosebaceous units. During normal mammary gland organogenesis , BMPs are likely used by the nipple epithelium to suppress keratinocyte differentiation , thus preventing the formation of pilosebaceous units. In this report , we characterize the morphology and processes that influence the development of hairs within the nipple of the KRT14-Noggin mouse. We demonstrate that Noggin acts , in part , by reducing the BMP signal in the epithelium. Reduction of the BMP signal in turn leads to a reduction in the levels of parathyroid hormone-related protein. We propose that during evolution of the nipple, the BMP pathway was co-opted to suppress hair follicle formation and create a more functional milk delivery apparatus.