Abstract

The skin constantly renews itself throughout adult life, and the hair follicle undergoes a perpetual cycle of growth and degeneration. Stem cells (SCs) residing in the epidermis and hair follicle ensure the maintenance of adult skin homeostasis and hair regeneration, but they also participate in the repair of the epidermis after injuries. We summarize here the current knowledge of epidermal SCs of the adult skin. We discuss their fundamental characteristics, the methods recently designed to isolate these cells, the genes preferentially expressed in the multipotent SC niche, and the signaling pathways involved in SC niche formation, SC maintenance, and activation. Finally, we speculate on how the deregulation of these pathways may lead to cancer formation.

Keywords: hair follicle, multipotency, self-renewal, cell fate determination, Wnt signaling, Bmp, cancer

Skin and its appendages ensure a number of critical functions necessary for animal survival. Skin protects animals from water loss, temperature change, radiation, trauma, and infections, and it allows animals to perceive their environment through tactile sense. Through camouflage, the skin provides protection against predators, and it also serves as decoration for social and reproductive behavior.

Adult skin is composed of a diverse organized array of cells emanating from different embryonic origins. In mammals, shortly after gastrulation, the neurectoderm cells that remain at the embryo surface become the epidermis, which begins as a single layer of unspecified progenitor cells. During development, this layer of cells forms a stratified epidermis (sometimes called interfollicular epidermis), the hair follicles (HRs), sebaceous glands, and, in nonhaired skin, the apocrine (sweat) glands. Mesoderm-derived cells contribute to the collagen-secreting fibroblasts of the underlying dermis, the dermovasculature that supplies nutrients to skin, arrector pili muscles that attach to each hair follicle (HF), the subcutaneous fat cells, and the immune cells that infiltrate and reside in the skin. Neural crestderived cells contribute to melanocytes, sensory nerve endings of the skin, and the dermis of the head. Overall, approximately 20 different cell types reside within the skin.

In the adult, many different types of stem cells (SCs) function to replenish these various cell types in skin as it undergoes normal homeostasis or wound repair. Some SCs (e.g., those that replenish lymphocytes) reside elsewhere in the body. Others (e.g., melanoblasts and epidermal SCs) reside within the skin itself. This review concentrates primarily on epidermal SCs, which possess two essential features common to all SCs: They are able to self-renew for extended periods of time, and they differentiate into multiple lineages derived from their tissue origin (Weissman et al. 2001).

Mature epidermis is a stratified squamous epithelium whose outermost layer is the skin surface. Only the innermost (basal) layer is mitotically active. The basal layer produces, secretes, and assembles an extracellular matrix (ECM), which constitutes much of the underlying basement membrane that separates the epidermis from the dermis. The most prominent basal ECM is laminin5, which utilizes 31-integrin for its assembly. As cells leave the basal layer and move outward toward the skin surface, they withdraw from the cell cycle, switch off integrin and laminin expression, and execute a terminal differentiation program. In the early stages of producing spinous and granular layers, the program remains transcriptionally active. However, it culminates in the production of dead flattened cells of the cornified layer (squames) that are sloughed from the skin surface, continually being replaced by inner cells moving outward ().

Epidermal development and hair follicle morphogenesis. The surface of the early embryo is covered by a single layer of ectodermal cells that adheres to an underlying basement membrane of extracellular matrix. As development proceeds, the epidermis progressively stratifies and acquires layers of terminally differentiating cells that are required to establish a functional barrier. During embryonic development, some of the undifferentiated basal cells are instructed by the underlying dermis (signal 1) to adopt a hair follicular fate. Subsequently, the epidermis sends a message to the dermis (signal 2) to make the dermal papilla (DP). Finally, the DP sends a message to the developing follicle (signal 3), allowing its growth and differentiation to form the discrete lineages of the hair follicle and its hair. Encased by a basement membrane, the basal layer of the follicle is referred to as the outer root sheath (ORS). At the base of the mature follicle is the highly proliferative compartment called the matrix (Mx). Matrix cells differentiate to form the concentric rings of differentiating cells that give rise to the hair shaft, its channel (the inner root sheath, IRS), and the companion layer. Hair follicles also contain sebaceous glands to ensure the water impermeability of the hair and lubricate the hair channel and skin surface.

The major structural proteins of the epidermis are keratins, which assemble as obligate heterodimers into a network of 10-nm keratin intermediate filaments (IFs) that connect to 64-integrin-containing hemidesmosomes that anchor the base of the epidermis to the laminin5-rich, assembled ECM. Keratin IFs also connect to intercellular junctions called desmosomes, composed of a core of desmosomal cadherins. Together, these connections to keratin IFs provide an extensive mechanical framework to the epithelium (reviewed in Omary et al. 2004). The basal layer is typified by the expression of keratins K5 and K14 (also K15 in the embryo), whereas the intermediate suprabasal (spinous) layers express K1 and K10. Desmosomes connected to K1/K10 IFs are especially abundant in suprabasal cells, whereas basal cells possess a less robust network of desmosomes and K5/K14. Rather, basal cells utilize a more dynamic cytoskeletal network of microtubules and actin filaments that interface through -and -catenins to E-cadherin-mediated cell-cell (adherens) junctions, in addition to the 1-integrin-mediated cell-ECM junctions (reviewed in Green et al. 2005, Perez-Moreno et al. 2003). Filaggrin and loricrin are produced in the granular layer. The cornified envelope seals the epidermal squames and provides the barrier that keeps microbes out and essential fluids in (Candi et al. 2005, Fuchs 1995) (). The program of terminal differentiation in the epidermis is governed by a number of transcription factor families, including AP2, AP1, C/EBPs, Klfs, PPARs, and Notch (reviewed in Dai & Segre 2004).

Although the molecular mechanisms underlying the process of epidermal stratification are still unfolding, several studies have recently provided clues as to how this might happen. Increasing evidence suggests the transcription factor p63 might be involved. Mice null for the gene encoding p63 present an early block in the program of epidermal stratification (Mills et al. 1999, Yang et al. 1999).

There are several possible mechanisms by which stratification could be achieved with an inner layer of mitotically active cells and suprabasal differentiating layers. In the first mechanism, a proliferating basal cell progressively weakens its attachment to the basement membrane and to its neighbors and is pushed off the basal layer and up into the spinous layer. In vitro studies demonstrated that this process, referred to as delamination, effectively allows stratification (Vaezi et al. 2002, Watt & Green 1982). A possible alternative to delamination is that basal cells in a stratifying tissue might orient their mitotic plane of division perpendicular to the underlying basement membrane, which would consequently place one of the two daughter cells in the suprabasal layer.

Recent studies in mice suggest that during embryonic development in skin, the majority of mitotic cells within the epidermis go from having their spindle plane parallel to the basement membrane to a perpendicular orientation (Lechler & Fuchs 2005, Smart 1970). In these perpendicular orientations, the apical centriole associates with a complex containing Nuclear Mitotic Apparatus protein, partitioning-defective protein 3, atypical protein kinase C, Inscuteable, and partner of inscuteable. The association with this cortical complex is intriguing because most of these evolutionarily conserved proteins have been shown genetically to be essential for the asymmetric cell divisions that occur in Drosophila neuroblasts and in Caenorhabditis elegans embryos (Cowan & Hyman 2004, Wodarz 2005). Although many features of the underlying mechanism remain to be addressed, proper spindle orientation appears to require 1-integrin and -catenin, further underscoring the importance of basement membrane and adherens junctions in the establishment of epidermal polarity and tissue architecture (Lechler & Fuchs 2005). More studies are now needed to determine the respective role of asymmetrical cell division and delamination during development, skin homeostasis, and pathological conditions such as wound healing.

The development of HFs involves a temporal series of epithelial-mesenchymal interactions (reviewed in Hardy 1992) (). First, the dermis signals to the overlying epidermis to make an appendage. In response, the epidermis then transmits a signal to instruct the underlying dermal cells to condense and form the dermal papilla (DP). Another signal is then sent from the DP to promote the proliferation and elaborate differentiation required to form the epidermal appendage.

The process of HF development has been divided into discrete stages distinguished by their morphological and biochemical differences (Paus et al. 1999). The first morphological sign of HF development is the formation of a hair placode, in which the basal epithelium becomes elongated and invaginates at sites where dermal condensates form. As the developing follicle extends downward and en-wraps the DP, the cells at the base maintain a highly proliferative state. During follicle maturation, these proliferating (matrix) cells begin to differentiate into the inner root sheath (IRS), which is the envelope for the future hair shaft and is marked by the expression of the transcription factor GATA3 and the structural protein trichohyalin (Kaufman et al. 2003, O'Guin et al. 1992). The outer layer of cells becomes the outer root sheath (ORS), which is contiguous with the epidermis and is surrounded externally by the basement membrane. The ORS expresses K5 and K14, similar to the interfollicular epidermis. As the follicle continues to widen, a new inner core of cells appears and begins to express the hair keratin genes of the hair shaft (reviewed in Omary et al. 2004). By postnatal day 8 in mice, follicle downgrowth is complete, and for the next 7 days, matrix cells proliferate and differentiate into the six concentric layers of the IRS and hair shaft ().

At postnatal day 16, proliferation in the matrix ceases, and the lower two-thirds of the HF rapidly degenerates by a process involving apoptosis (catagen stage). An epithelial strand surrounded by the retracting basement membrane draws the DP upward, where in backskin it comes to rest just below the base of this permanent segment of the HF called the bulge. This resting stage is referred to as telogen. In the first hair cycle, telogen lasts approximately one day, but in subsequent cycles, this phase becomes increasingly extended, suggesting the need to reach a biochemical threshold before the next hair cycle can be activated. The new cycle of hair regeneration (anagen) begins with the emergence of a proliferating hair germ, and the progression to form the mature follicle bears a significant resemblance to embryonic folliculogenesis (Muller-Rover et al. 2001) (). The periodic cycling of hair growth and degeneration persists throughout the life of the animal and implicates the existence of SCs to fuel the regenerative process.

The hair follicle cycle. When matrix cells exhaust their proliferative capacity or the stimulus required for it, hair growth stops. At this time, the follicle enters a destructive phase (catagen), leading to the degeneration of the lower two-thirds of the follicle. The upper third of the follicle remains intact as a pocket of cells surrounding the old hair shaft (club hair). The base of this pocket is known as the bulge, which is the natural reservoir of hair follicle stem cells (SCs) necessary to form a new hair follicle. After catagen, the bulge cells enter a quiescent stage (telogen), in which the DP is now in close contact with bulge SCs. In the mouse, the first telogen lasts approximately one day, after which all the hair follicles synchronously enter a new cycle of regeneration and hair growth (anagen stage). The bulge as a structure develops when the new hair must emerge from the original orifice, which is often shared by the old club hair. Subsequent hair cycles involve increasingly longer telogen phases, resulting in considerably less synchronous hair cycles.

The molecular mechanisms that govern HF morphogenesis and cycling are still poorly understood, but genetic studies in mice reveal the importance of Wnt/-catenin, bone morphogenetic protein (Bmp), sonic hedgehog (Shh), fibroblast growth factor (Fgf), epidermal growth factor receptor (Egf), NFkB, and Notch signaling pathways (reviewed in Millar 2002, Schmidt-Ullrich & Paus 2005).

The adult skin epithelium is composed of molecular building blocks, each of which consists of a pilosebaceous unit (HF and sebaceous gland) and its surrounding interfollicular epidermis (IFE). The IFE contains its own progenitor cells to ensure tissue renewal in the absence of injury, and HFs contain multipotent SCs that are activated at the start of a new hair cycle and upon wounding to provide cells for HF regeneration and repair of the epidermis.

The IFE, which generates the lipid barrier of adult skin, constantly renews its surface throughout the entire life of the animal and also undergoes reepithelialization after wound injuries. These renewing and repairing activities of the skin epidermis imply the existence of SCs to ensure these critical functions. Histological analysis has shown that mouse epidermis is organized in stacks of cells with a hexagonal surface area lying on a bed of ten basal cells (Mackenzie 1970; Potten 1974, 1981). This structure was hypothesized to function as an epidermal proliferative unit (EPU) with one putative SC per unit. Researchers tested experimentally the existence of EPUs using lineage-tracing analyses. The first type of lineage tracing was performed by infecting cultured mouse and human keratinocytes with a retrovirus expressing LacZ and grafting these marked keratinocytes onto immunodeficient mice. Alternatively, mice were directly infected with LacZ-virus in skin, following dermabrasion (Ghazizadeh & Taichman 2001, Kolodka et al. 1998, Mackenzie 1997). Analysis of the chimeric skin revealed the presence of discrete columns of blue cells from the basal cells to the most differentiated uppermost layer of cells. These findings demonstrate that EPUs exist in the basal IFE and can be maintained individually as a separate unit for extended periods of time. Such domains can be explained by a mechanism whereby basal cells divide asymmetrically relative to the basement membrane to maintain a proliferative daughter and give rise to a differentiating daughter cell overlying it (Lechler & Fuchs 2005).

Self-renewal within the epidermis has also been studied using genetic fate mapping, which circumvents the wound response generated in transplantation experiments (Ro & Rannala 2004). In this case, transgenic mice were engineered to express a mutant form of green fluorescent protein (GFP) that cannot be translated owing to the presence of a stop codon in the EGFP-coding sequence. Subsequently, the mice received topical application of a mutagen to induce mutations that can remove the stop codon and restore expression of a functional GFP protein. These sporadic mutations resulted in patches of GFP-positive cells within the IFE, allowing the visualization of EPU columns. Although elegant, these experiments did not address how many SCs are present in each EPU and where the SCs reside within the unit.

In human skin, the epidermis is thicker and undulates to form deep epidermal ridges (rete ridges) that extend downward in the epidermis and help to anchor the epidermis to the dermis. Used only sparingly, SCs have been proposed to cycle less frequently. The infrequently cycling cells within the IFE are located at the base of these ridges, which is conveniently in a more protected site than elsewhere within the IFE (Lavker & Sun 1982).

To identify characteristics of IFE SCs, researchers have turned toward in vitro experiments. Cultured human IFE keratinocytes expressing the highest level of 1-integrin have the highest proliferative potential in vitro (Jones & Watt 1993). Other genes have also been shown to be preferentially expressed in 1-enriched human keratinocytes, underscoring the biochemical distinctions of this population of basal cells (Legg et al. 2003). As would be expected, the 1-bright cells are found in the basal layer, but interestingly, they reside in clusters (Jones et al. 1995). Additionally, the 1-bright cells do seem to reside at the base of the deepest epidermal ridges of palmoplantar skin, consistent with the location of slow-cycling SCs observed by Lavker & Sun (1982). Elsewhere, however, the 1-bright clusters reside outside these zones, in a seemingly more compromised position for SCs. Hence, the extent to which 1-integrin levels define the distinguishing features of IFE SCs must await further studies. In this effort, additional markers are needed to enrich the purification and analyses of IFE cells with high proliferative potential. Such markers should also help in defining the location and the number of IFE SCs within their functional EPU columns and in discerning the extent to which less frequent cycling is a measure of stemness within the IFE population. A final issue to be resolved is the extent to which cells with high proliferative potential in the basal layer of the IFE are able to contribute to other cell lineages, i.e., those of the sebaceous gland and HF.

In the mid-1970s, Rheinwald & Green (1975) defined culture conditions allowing the growth of human IFE SCs in vitro. This seminal discovery allowed the propagation of keratinocytes from severely burned patients and their subsequent grafting as sheets of autologous cultured cells that were functional in reepithelializing the damaged skin (Gallico et al. 1984, O'Connor et al. 1981, Pellegrini et al. 1999, Ronfard et al. 2000). In the past 25 years, this technology has saved many lives. Although the patient's repaired skin epithelium does not regenerate sweat glands or HFs, it does have a normal epidermis, which can undergo wound repair.

When plated at low cell density, cultured human keratinocytes can form three types of colonies: (a) highly proliferative colonies (holoclones) of small round cells that present an undifferentiated morphology and that can be passaged long-term, (b) aborted colonies (paraclones) displaying large flat morphology typical of terminally differentiated cells, and (c) relatively small heterogeneous colonies (meroclones) of limited proliferative potential that become senescent after a few rounds of passaging (Barrandon & Green 1987). Although the term holoclone refers only to the proliferative capacity of the colony, the progeny of a single epidermal holoclone in vitro can re-form a functional and renewable epidermis in vivo (Rochat et al. 1994). This implies that at least some cells within holoclones possess the fundamental characteristics of a SC in that they can self-renew and differentiate into a functional tissue. By contrast, meroclones have been likened to so-called transit-amplifying cells, i.e., cells with a limited number of cell divisions before they commit to terminally differentiate. Although the precise physiological relevance of these cultured populations of cells remains to be determined, the in vitro description of their clonal properties has served as a useful foundation for the analyses of SCs in vivo.

In the hair follicle, SCs reside in a discrete microenvironment called the bulge, located at the base of the part of the follicle that is established during morphogenesis but does not degenerate during the hair cycle. Bulge SCs are more quiescent than other cells within the follicle. However, during the hair cycle, bulge SCs are stimulated to exit the SC niche, proliferate, and differentiate to form the various cell types of mature HFs. In addition, to provide cells during HF regeneration, the bulge SC is a reservoir of multipotent SCs that can be recruited during wound healing to help the repair of the epidermis. We summarize here the recent progress in the functional and molecular characterization of bulge SCs.

For many years, it was thought that the SCs that regenerate HFs during the hair cycle are the highly proliferative matrix cells (Kligman 1959). This model was later challenged when Montagna & Chase (1956) observed that X-ray irradiation kills the matrix cells, but hairs can still re-form from cells within the ORS. The ability of the upper ORS to act in concert with the DP to make HFs was further substantiated by dissection and transplantation experiments (Jahoda et al. 1984; Oliver 1966, 1967).

Mathematical modeling has supported the notion that SCs may be used sparingly and hence divide less frequently than their progeny (Potten et al. 1982). This notion was bolstered by administering repeated doses of marked nucleotide analogs such as BrdU or 3[H]-thymidine to label the S-phase cycling cells of the skin (pulse period) and then following the fate of the incorporated label over time (chase period). The differentiating cells are sloughed from the skin surface, and the more proliferative cells dilute their label as they divide, marking the least proliferative cells as label-retaining cells (LRCs) (Bickenbach 1981).

To locate HF LRCs, Lavker and colleagues (Cotsarelis et al. 1990) administrated BrdU for a week in newborn mice and then analyzed label retention in the skin after four weeks of chase. The majority of LRCs in the skin resided in a specialized region at the base of the permanent segment of the HF. Known as the bulge, this region was described more than a century ago by histologists (Stohr 1903). Within the ORS, the bulge resides just below the sebaceous gland at a site where the arrector pili muscle attaches to the follicle (). Although its origins are likely to be traced to the early stages of HF embryogenesis, the bulge acquires its distinctive appearance when the first postnatal hair germ emerges before the prior club hair has been shed (). During the first telogen phase, a single layer of quiescent cells surround the old club hair; as the new hair cycle initiates, the bulge acquires a second layer of cells (Blanpain et al. 2004).

Although generally quiescent, bulge cells can be prompted to proliferate artificially in response to mitogenic stimuli such as phorbol esters (TPA) or naturally at the start of each hair cycle. In an elegant double-label study to demonstrate a precursor-product relation, Taylor et al. (2000) showed that when BrdU-labeled LRCs in the bulge are exposed to a brief pulse of a second nucleotide label, they incorporate 3[H]-thymidine as they exit and proliferate to develop the new hair germ. To directly determine whether the bulge region contains SCs, Barrandon and coworkers (Kobayashi et al. 1993) dissected rat and human HFs and assessed the growth potential of different HF segments in vitro. In rat-whisker follicles, 95% of the derived holoclones came from cells of the bulge segments, whereas less than 5% of the growing colonies could be derived from the matrix region. In adult human skin, keratinocytes with high proliferative potential were also found within bulge segments, but the zone of clonogenic cells was broader, extending from the bulge to the lower ORS (Rochat et al. 1994). In this regard, in adult human skin, the bulge is notably a less distinctive structure than it is in rodents.

Early studies involving reepithelialization during wound repair led researchers to posit that HFs may have the capacity to regenerate epidermis upon injury (Argyris 1976). To evaluate whether bulge LRCs have this capacity, Taylor et al. (2000) extended their double-labeling techniques to wound-healing experiments. Indeed, following a wound, BrdU-labeled cells derived from the bulge could be found proliferating within the epidermis near the HF orifice (infundibulum).

Fuchs and coworkers (Tumbar et al. 2004) recently adapted the nucleotide pulse-chase experiments to the protein level by engineering mice expressing a tetracycline-regulated histone H2B-GFP protein in their skin epithelium. In the absence of tetracycline, all the skin epithelial nuclei were green with H2B-GFP expression, but when tetracycline was administered, the gene was shut off, and after four weeks, only the bulge cells still labeled brightly with H2B-GFP protein (). Upon wounding, H2B-GFP-positive cells were detected in the epidermis and infundibulum, confirming the ability of bulge LRCs to reepithelialize the epidermis in response to injury (Tumbar et al. 2004). Upon activation of the hair cycle, the emerging hair germ displayed H2B-GFP-positive cells with much weaker fluorescence than the bulge, suggesting that they were derived from the bulge LRCs. These findings support the studies of Barrandon, demonstrating the ability of bulge cells to regenerate the HF during the normal hair cycle.

The bulge stem cells (SCs). Bulge (Bu) SCs are more quiescent than are other keratinocytes with proliferative potential in the skin. Tumbar et al. (2004) developed a strategy for conducting fluorescent pulse-chase experiments in mice engineered to express a tetracycline-regulatable H2B-GFP transgene. After labeling all the skin epithelial cells with H2B-GFP, a four-week chase resulted in significant H2B-GFP-label retention only in the bulge (a). Label-retaining cells (LRCs) could be found along the basal layer of cells that express 64-integrins, as well as in a suprabasal location within the bulge (b). Bulge SCs express a high level of the cell surface protein CD34, which has been used with 6-integrin to isolate basal and suprabasal bulge cells, using flow cytometry (Blanpain et al. 2004, Trempus et al. 2003). [The approximate fluorescence of the outer root sheath (ORS) and interfollicular epidermis (IFE) cells is also indicated on the FACS profile.] Tissues were counterstained with Dapi (blue) to mark the nuclei. Abbreviations used: Cb, club hair; HF, hair follicle; SG, sebaceous gland.

Several lines of evidence suggest that there is a continuous flux of bulge cells throughout the growing stage of the hair cycle. During the anagen phase of the backskin hair cycle, Tumbar et al. (2004) detected a trail of H2B-GFP-positive cells along the lower ORS. Although these cells were less bright than their bulge LRC counterparts, the results were intriguing in light of rat-whisker bulge transplantation and clonogenic experiments performed by Barrandon and colleagues (Oshima et al. 2001). Based on these seminal studies, researchers proposed that SCs migrate from the bulge along the basal layer of the ORS to the matrix, where they proliferate and differentiate to produce the hair and IRS. Although the hair cycle of whisker follicles differs from those in the backskin in that the growing stage is longer and follicles transit from mid-catagen directly to anagen, a common theme for SC movement and activation likely applies for HFs, irrespective of whether they are whisker or pelage follicles.

In the past ten years, researchers have made considerable strides in isolating and purifying cells from the HF bulge. Given the complexity of the skin, purification of bulge cells using flow cytometry (FACS) has focused on isolating bulge cells in the simpler, telogen-phase follicles, where the quiescent bulge marks the base. Kaur and colleagues (Li et al. 1998) have employed conjugated antibodies against 6-integrin and anti-CD71 (antitransferin Ab or 10G7) to show that 6-bright, CD71-dim cells from skin possess similar colony-forming efficiency but higher long-term growth potential than the rest of the population. Bulge LRCs share this expression pattern and are enriched in the 6-bright, CD71-dim population by approximately twofold (Tani et al. 2000). Other markers such as S100A4 and S100A6 proteins (Ito & Kizawa 2001), K19 (Michel et al. 1996), K15 (Lyle et al. 1998), and CD34 (Trempus et al. 2003) have also been reported to exhibit preferential expression in the bulge. Although most of these antibodies have not proven useful for isolating living bulge cells by FACS, CD34 is an exception. CD34-positive cells are enriched tenfold for LRCs, and they form larger colonies than unfractionated epidermis (Trempus et al. 2003).

When transgenic expression of a basal epidermal marker (K14-GFP) is used in conjunction with antibodies against 6-integrin and CD34, purification of bulge cells is enhanced substantially (Blanpain et al. 2004). On the basis of differential 6 expression, the CD34/K14-GFP-positive cells from the inner and outer layers of the mature bulge can also be fractionated (). Bulge cells have also been purified from K15-GFP-transgenic skin in conjunction with 6-integrin antibodies (Morris et al. 2004), and when tetracycline-regulatable H2B-GFP mice are employed for bulge purification, a 70-fold enrichment of bulge LRCs can be achieved over unfractionated skin epithelial cells (Tumbar et al. 2004). In all three of these methods for obtaining bulge cells with high purity, bulge cells form large colonies that can be passaged in vitro (Morris et al. 2004, Tumbar et al. 2004). This is true for both the inner and the outer layer of the bulge (Blanpain et al. 2004) (). Clonogenicity studies further demonstrate that a large colony derived from a single bulge cell can give rise to multiple large colonies upon passaging, implying the occurrence of SC self-renewal in vitro (Blanpain et al. 2004, Claudinot et al. 2005).

The two major properties of SCs are their abilities to self-renew and to differentiate along multiple lineages. To address the differentiation potential of bulge SCs, researchers have used a variety of methods, including (a) transplantation studies of microdissected HF segments, (b) direct transplantation and clonal analysis of isolated bulge cells, and (c) genetic fate mapping in mice.

In pioneering studies, Oshima et al. (2001) generated chimeric rodent-whisker follicles by removing the unlabeled bulge of a wild-type vibrissae follicle, replacing it with a lacZ-expressing bulge microdissected from a transgenic mouse-whisker follicle and transplanting the chimeric follicle into the kidney capsule and/or embryonic backskin from immunodeficient mice. Thirty days after transplantation, lacZ-marked cells were detected in the epidermis, sebaceous gland, and HFs (Oshima et al. 2001). Morris et al. (2004) have obtained similar results using 105-FACS-isolated K15-GFP-tagged bulge cells transplanted into immunodeficient mice.

In the experiments of Barrandon and coworkers, temporal analysis of anagen-phase chimeric whisker follicles revealed a downward flux of lacZ-positive cells originating from the transplanted bulge, migrating to the matrix and subsequently differentiating into one of the six concentric rings of IRS and hair shaft lineages. Although at reduced frequency, cells residing in the lower HF were also able to differentiate into multiple skin cell lineages (Oshima et al. 2001). These findings support the view that SCs migrate from the bulge to the base of the follicle before they differentiate and lose their potential. As outlined above, it still remains to be resolved as to whether a continuous downward flux of bulge cells occurs only in whiskers or human HFs, in which the hair cycle displays a prolonged anagen phase, or whether it is a feature common to all HFs.

The studies above beautifully underscore the potential of cells within the bulge region to differentiate along the three different lineages afforded to the skin keratinocyte. However, they do not address whether the bulge consists of multiple types of unipotent progenitors, each of which are able to differentiate along one lineage, or whether individual bulge cells possess multipotency, the ability to differentiate along any of the three lineages. To date, technical hurdles have precluded testing for multipotency using in vivo clonal analyses. However, in the past few years, researchers have employed clonal analyses in vitro to demonstrate definitively the multipotency of bulge cells when passaged in vitro (Blanpain et al. 2004, Claudinot et al. 2005).

In the first study, Fuchs and coworkers (Blanpain et al. 2004) placed isolated K14-GFP-tagged bulge cells in culture to obtain individual holoclones. After short-term expansion, the descendents from a single bulge cell were then transplanted onto the backs of nude mice. The progeny of single bulgederived holoclones each gave rise to GFP-positive HFs, IFE, sebaceous gland, and even bulge SCs (Blanpain et al. 2004). Similar results were obtained by Barrandon and coworkers (Claudinot et al. 2005), who were able to generate thousands of HFs from the progeny of a single cultivated rat-whisker SC. These experiments provide compelling evidence in support of the notion that cells within the adult follicle bulge possessing the classical criteria of bona fide multipotent SCs. That the inner bulge layer also has this capacity further suggests that even when bulge cells detach from the basal lamina and appear to undergo early commitment to the HF lineage, the process is reversible, at least after in vitro culture (Blanpain et al. 2004).

Under normal circumstances, the bulge acts as a reservoir of follicle SCs, and only in response to injury has it been shown to mobilize and function as a multipotent SC reservoir. Whether there are other multipotent SCs in adult skin remains to be demonstrated. However, there is substantial evidence that unipotent SCs exist in other locations in the skin. Fate-mapping experiments using a Cre recombinase that permanently marks bulge cells reveal that under physiological conditions, the IFE contains only rare patches of -galactosidase-positive cells derived from bulge cells. These data reinforce the notion postulated above on the basis of EPU columns: Normal IFE homeostasis is controlled by the presence of unipotent progenitors that reside within the IFE (Ito et al. 2005, Levy et al. 2005, Morris et al. 2004). That bulge SCs are not necessary for epidermal homeostasis is perhaps best exemplified by the fact that palmoplantar skin lacks HFs altogether, as do a number of genetic hair disorders, yet epidermal homeostasis and wound repair can still take place (Montagna et al. 1954).

To determine which genes and signaling pathways operate within the bulge SCs, researchers have performed transcriptional profiling on isolated telogen-phase bulge cells (Blanpain et al. 2004, Morris et al. 2004, Tumbar et al. 2004). In most cases, these profiles have been compared with those of basal epidermal cells, which have proliferative capacity but are thought to contain few if any multipotent SCs. Notably, most of the transcripts upregulated in either the Tumbar or Morris arrays were upregulated in the Blanpain array, which encompassed a considerably larger gene set compared with the two earlier studies. Blanpain et al. (2004) list 56 transcripts that scored as upregulated in bulge cells irrespective of the isolation method, hair cycle stage, or attachment to the basal lamina and that can be viewed as a molecular signature of bulge cells.

Interestingly, 14% of genes found to be upregulated in other types of SCs (hematopoeitic SC, neuronal SC, and embryonic SC) (Ivanova et al. 2002, Ramalho-Santos et al. 2002) were also found to be a part of the bulge signature (Blanpain et al. 2004), suggesting that certain genes within this list are likely involved in the unique properties common to many if not all SCs. Related to this issue are the important similarities recently uncovered between these mouse bulge SC profiles and those of human bulge SCs (Ohyama et al. 2006). Although some differences were noted (CD34, for example, extends to the lower ORS in human follicles), this similarity bodes well for future clinical studies aimed at improving the potential of skin SCs for therapeutic purposes.

The bulge signature now provides a constellation of markers that should enable researchers to examine the extent to which bulge cells retain their program of gene expression as they respond to natural stimuli, e.g., during the hair cycle and upon injury, and as they exit the niche to migrate and/or differentiate along particular lineages. The list should also be useful in examining how the bulge cells change their properties in response to various genetic manipulations. Through such future examinations, scientists should begin to uncover the extent to which the bulge signature is a reflection of the quiescence of these SCs and identify the subset of these genes involved in self-renewal and in suppression of lineage determination irrespective of whether a skin SC is quiescent or proliferative.

Although these studies are in their infancy, a few important lessons are already emerging. One intriguing aspect of the transcriptional profiling conducted on the bulge to date is the high degree to which the bulge signature is maintained in both anagen and telogen stages of the hair cycle and in basal and suprabasal bulge layers (Blanpain et al. 2004). These findings underscore the powerful influence that the microenvironment of the bulge niche has on its residents. In turn, for a bulge SC to become mobilized and exit the niche, this dominance must be overcome.

Although researchers are conducting additional experiments to dissect the molecular significance of the bulge signature, it is tempting to speculate on the roles of various transcripts that are either up- or downregulated preferentially in the bulge. To this end, a number of bulge signature genes encode cell adhesion, cytoskeleton, and ECM components. We posit that these genes may reflect the specialized microenvironment that must be suitable not only for maintaining their SC characteristics within the niche, but also for allowing bulge SCs to exit their niche and migrate during wound repair and/or in hair regrowth.

The bulge signature also provides a battery of candidate genes likely to play a role in SC quiescence. Most notable are the many upregulated genes encoding cell-cycle inhibitory factors, such as Cdkn1b (p27), Cdkn1c (p57), and Cdkn2b (p15), and the numerous downregulated genes encoding cell-cycle-promoting factors, such as Ki67, proliferating cell nuclear antigen, cyclins (Cyclin D1, D2, A2, B1) and cyclin-dependent kinases, and cell-division-cycle-related genes (Cdc2a, 2b, 6, 7, 25c) (Blanpain et al. 2004, Morris et al. 2004, Tumbar et al. 2004). Although the cell cycle is typically thought to be regulated largely at the posttranslational level, the transcriptional regulation of these cell-cycle genes suggests that the quiescent nature of the bulge is governed by unique operational control mechanisms.

Finally, another interesting set of bulge signature genes contains those that are likely involved in maintaining the SCs in an undifferentiated, growth-inhibited state. Of these genes, it is particularly interesting that many components of the Wnt/-catenin signaling pathway (Tcf3; Tcf4; Dkk-3; sFRP1; Fzd 2, 3, 7; Dab2; Ctbp2) and the TGF-/Bmp signaling pathways (Ltbp1, 2, 3; Tgf-2; Gremlin) are upregulated in the bulge. These pathways are discussed individually in the sections below.

The Wnt/-catenin signaling pathway is conserved throughout the eukaryotic kingdom, where it controls a myriad of different cellular decisions during embryonic and postnatal development (). Wnt deregulation leads to an imbalance of proliferation and differentiation, often resulting in cancers (Reya et al. 2001).

The Wnt/-catenin signaling pathway during hair follicle (HF) morphogenesis and regeneration. (a) Schematic of the canonical Wnt pathway (for more details, see http://www.stanford.edu/%7Ernusse/). In the absence of a Wnt signal, the excess of cytoplasmic -catenin is targeted for degradation through its association with a multiprotein complex. Upon binding Wnt, its activated receptor complex recruits certain key components of the -catenin degradation targeting machinery. Stabilized free cytoplasmic -catenin is now translocated to the nucleus, where it can associate with transcription factors of the LEF/TCF family to transactivate the expression of their target genes. (b) Loss- and gain-of-function studies in mice have highlighted the different functions of Wnt/-catenin signaling during morphogenesis and adult skin homeostasis. During HF morphogenesis, Wnt/-catenin is required to specify the HF (placode) fate in the undifferentiated basal epidermis. During the adult hair cycle, Wnt/-catenin is required to maintain HF stem cell (SC) identity. As judged by a Wnt reporter transgene, an increase in Wnt signaling promotes SC activation to initiate the growth of a new hair during the telogen-to-anagen transition. An even stronger signal appears to be involved later at the transition of matrix cells to commit to terminally differentiate specifically along the hair shaft lineage. (c) When a constitutively active form of -catenin is expressed for sustained periods in skin epidermis, mice develop de novo HFs from the interfollicular epidermis (IFE), outer root sheath (ORS), and sebaceous glands (SGs). Eventually, these mice develop HF tumors called pilomatricoma, which consist of immortalized matrix-like cells at the periphery, and pure hair cells in the centers (no inner root sheath or companion layer cells). Visualization was enhanced by breeding the K14-N mice on a background of K14-GFP mice. (d) The different signal strengths of Wnt reporter gene activity, combined with the -catenin dosage dependency associated with these different outcomes in mice, can be explained by a model whereby the effective strength of Wnt signaling controls the behavior and fate of the follicle SC. Note: The so-called gradient of Wnt activity refers to the status of Tcf/Lef/-catenin transcriptional activity within the cell, which in fact could be achieved as a gradient, without even involving a Wnt per se. DP, dermal papilla.

Wnts compose a large family of cysteine-rich secreted glycoproteins that activate Frizzled receptors, which in turn stimulate a cascade of events culminating in the stabilization and accumulation of cytoplasmic -catenin. Normally, cellular -catenin is complexed with E-cadherin and -catenin at adherens junctions, and free cytoplasmic -catenin is degraded by the proteasome. Upon Wnt signaling, excess -catenin is no longer degraded, and it is free to complex with and activate members of the Tcf/Lef1 family of transcription factors (Logan & Nusse 2004) ().

The sonic hedgehog (Shh) signaling pathway during hair follicle morphogenesis and adult hair cycle. (a) Schematic of the Shh pathway. In the absence of Shh, its receptor Patched (Ptch) inhibits Smoothened (Smo) activity. Upon Shh binding, Ptch can no longer repress Smo, which activates the translocation of Gli into the nucleus, allowing it to transactivate its target genes. (b) The role of Shh in the hair follicle. Loss-of-function studies in mice have revealed the importance of Shh in sustaining proliferation in the embryonic and adult hair germ. Gain-of-function studies underscore the striking relation between basal cell carcinomas and deregulation of the Shh pathway. (c) Shh is not expressed in the quiescent bulge stem cells. During hair regeneration, there is a lag before Shh is strongly activated in the developing hair germ. Sustained expression of Shh seems to rely on close association with the dermal papilla (DP). Both in embryonic development and the adult, Shh appears to act downstream of the Wnt/-catenin signaling pathway. Bu, bulge; HG, hair germ.

In the skin, Wnt and -catenin play diverse roles in HF morphogenesis, SC maintenance and/or activation, hair shaft differentiation, and also pilomatricoma tumor formation in mice and humans (Alonso & Fuchs 2003). Activation of Wnt/-catenin signaling is critical during the first stage of HF morphogenesis, as evidenced by the absence of placode formation on conditional ablation of -catenin (Huelsken et al. 2001) or constitutive expression of a soluble Wnt inhibitor (Dkk1) (Andl et al. 2002). Although the source and identity of the putative Wnt signal required to induce placode formation remain elusive, it may be the first dermal signal to instruct epidermal cells to make hair. Consistent with this notion is the activation in both the placode and the postnatal hair germ of a Wnt reporter gene driving lacZ under the control of an enhancer composed of multimerized binding sites for the Lef1/Tcf DNA-binding proteins that interact with and are activated by association with -catenin (DasGupta & Fuchs 1999, Reya & Clevers 2005) (). Nuclear -catenin and Lef1 expression are also seen in embryonic placodes and postnatal hair germs at this time (Merrill et al. 2004, van Genderen et al. 1994, Zhou et al. 1995). Noggin, a soluble inhibitor of Bmps, is expressed by the mesenchymal condensate and is required in the early stage of HF morphogenesis and cycling. It appears to act at least in part by promoting expression of Lef1 (Botchkarev et al. 2001, Jamora et al. 2003).

Transgenic mouse studies support a role for Wnt signaling in the specification of HF development. Mice expressing a constitutively stabilized -catenin (>N-catenin) display de novo HFs (Gat et al. 1998) (), whereas mice lacking Lef1 (van Genderen et al. 1994) or -catenin (Huelsken et al. 2001) or overexpressing the Wnt inhibitor Dkk1 exhibit a paucity of follicles (Andl et al. 2002).

Postnatally, the strongest Wnt signal is associated with the terminally differentiating cortical cells of the hair shaft (DasGupta & Fuchs 1999) (). The hair keratin genes possess Lef1/Tcf DNA-binding domains and are bona fide targets for Wnt-mediated gene expression (Merrill et al. 2001, Zhou et al. 1995). This lineage of the matrix cells appears to be particularly singled out for robust Wnt signaling, as K14-N-catenin transgenic mice develop pilomatricomas, which are pure tumor masses of cortical cells (Gat et al. 1998). Similarly, the majority of human pilomatricomas possess N-terminal stabilizing mutations in the coding sequence of the -catenin gene (Chan et al. 1999, Xia et al. 2006).

In contrast to the cortical cells, the bulge is largely silent for Wnt reporter activity (DasGupta & Fuchs 1999). Microarray data suggest that the bulge is normally in a Wnt-inhibited environment, showing an upregulation of genes encoding putative Wnt-inhibitory factors (sFRP1, Dkk3, Wif) and a downregulation of genes encoding Wnt-promoting factors in the bulge (Wnt3, Wnt3a). However, bulge SCs express a number of frizzled surface receptors (Fz2, 3, and 7) to enable them to receive Wnt signals as well as Wnt-signaling-related transcription factors (Tcf3, Tcf4, Tle1, Ctbp2) to enable them to transmit a Wnt signal (see Tumbar et al. 2004). In this regard, Tcf3 is intriguing, as it has been shown to act as a repressor in the absence of Wnt signaling (Merrill et al. 2001, 2004). Taken together, these findings suggest that bulge SCs are in a quiescent, Wnt-inhibited state and that Wnt signaling plays a key role in driving these cells along at least one hair differentiation lineage ().

Several studies suggest that the role of Wnt signaling in the postnatal HF may be even broader. The involvement of Wnts in HF morphogenesis suggests that Wnt signaling may be important for activating bulge SCs. Consistent with this notion is the presence of a few Wnt-reporter-driven, LacZ-positive bulge cells at the beginning of the hair cycle (DasGupta & Fuchs 1999). The number of activated bulge cells can be considerably enhanced by breeding the Wnt-reporter mice on the background of K14-N-catenin mice; at most stages of the hair cycle, however, the bulge remains silent for Wnt-reporter activity (DasGupta & Fuchs 1999, Merrill et al. 2001).

By inducing the expression of stabilized -catenin in telogen-phase follicles, several groups have observed precocious activation of hair regeneration (Lo Celso et al. 2004, Lowry et al. 2005, Van Mater et al. 2003), in a fashion reminiscent of the de novo follicle morphogenesis that occurs in the IFE (Gat et al. 1998). Despite the premature transition from telogen to anagen, the K14-N-catenin bulge reenters its relatively quiescent state once the follicle has grown downward (Lowry et al. 2005). These findings imply that some additional factor(s) is required in addition to elevated Wnt signaling to change the status of Lef1/Tcf-regulated genes (including TopGal) and activate bulge SCs. It is tempting to speculate that this signal emanates from the DP, given the close proximity of the DP to the bulge prior to the start of the hair cycle. One candidate may be the Bmp-inhibitor Noggin, produced by the DP and shown to be required for Lef1 expression in the embryonic hair placode and in the matrix cells as well (Andl et al. 2004, Botchkarev et al. 1999, Jamora et al. 2003, Kobielak et al. 2003). Fgf7 and Fgf10 are additional candidates known to be expressed in the bulge and to have an impact on follicle morphogenesis (Guo et al. 1993, Petiot et al. 2003).

Despite the continuous presence of an elevated level of stabilized -catenin, the size of the SC niche does not change over time (Lowry et al. 2005). This means that if elevated -catenin promote the self-renewal of bulge SCs, it must be accompanied by an increase in the rate at which SCs exit the niche. Two factors consistent with this notion are that the rate of BrdU-label retention is reduced and the level of BrdU-label incorporation is enhanced in the K14-N-catenin bulge. That said, this increased proliferation appears to be manifested in precocious SC activation, as it was not accompanied by a noticeable increase in the length of the hair or the cellularity of HFs.

To understand how -catenin elevation can promote SC activation in the bulge, Lowry et al. (2005) conducted microarray analyses on telogen- or anagen-phase SCs isolated from N-catenin or wild-type follicles. Intriguingly, some telogen-phase bulge genes affected by N-catenin were similarly affected in the normal anagen-phase bulge, suggesting the transgene-induced changes may reflect natural changes that occur in the telogen-to-anagen transition of the hair cycle. Although further studies are needed to assess the extent to which this is the case, genes that surfaced in these arrays and that may play a role in Wnt-mediated bulge SC activation include Cyclin D2 (Ccnd2), Sox4, and Biglycan (Lowry et al. 2005). Another protein upregulated in the early anagen bulge appears to be the transcriptional corepressor Hairless, which has been proposed to function by blocking the expression of the soluble Wnt inhibitor Wise, which in turn may lead to Wnt-mediated SC activation (Beaudoin et al. 2005). An additional interesting twist is the recent study reporting that Shh is a downstream target of Wnt-mediated activation of follicle SCs (Silva-Vargas et al. 2005). Shh is particularly intriguing as a Wnt candidate, as it would integrate these two key signaling pathways essential for HF morphogenesis. That said, on the basis of the differential expression of direct Wnt target genes and Shh, it seems unlikely that Shh is a direct target for Wnt signaling in bulge cells (Lowry et al. 2005). We discuss the Shh pathway in greater depth below.

In summary, these findings delineate sequential roles for Wnt signaling in temporally regulating follicle SC lineages, perhaps in a fashion that depends on the level of the signal: (a) -catenin stabilization promotes bulge SC activation, proliferation, and induction of follicle regeneration; (b) -catenin stabilization promotes the specification of matrix cells to terminally differentiate along the hair (cortical) cell lineage; (c) -catenin stabilization promotes de novo HF morphogenesis; and (d) constitutively active -catenin expression results in pilomatricoma hair tumors. The particular fate selected by a follicle cell appears to depend on a constellation of intrinsic and extrinsic factors, which together influence the status of Tcf/Lef1-regulated genes. At the Wnt-inhibited end of the spectrum is SC quiescence, and at the constitutive Wnt end is tumorigenesis ().

Similar to Wnt/-catenin, Shh is an ancient signaling pathway involved in cell fate specification and proliferation during animal development (Taipale & Beachy 2001). The Shh transmembrane receptor is Patched (Ptch), which is active in the absence of Shh (). Ptch functions by inhibiting Smoothened (Smo), which is essential to transduce the Shh signal through the Gli family of transcription factors to induce target gene expression. Ptch itself is a Shh target gene, resulting in the localized sequestration of Shh and the restriction of long-range signaling (Casali & Struhl 2004).

Given the prominence of the Shh pathway in development and proliferation, it is not surprising to find that when deregulated, this pathway leads to tumorigenesis. Rubin et al. (2005) illuminated its importance in skin with the finding that Ptch1 gene mutations cause basal cell nevus syndrome, a hereditary predisposition to basal cell carcinomas (BCCs), the most common type of skin cancer in humans. In the skin, Ptch acts as a tumor suppressor gene, as loss of heterozygosity at the Ptch locus (chromosome 9q22.3) has been observed in sporadic BCC and BCCs isolated from patients with basal cell nevus syndrome (Gailani et al. 1996, Hahn et al. 1996, Johnson et al. 1996, Unden et al. 1996). Activating mutations in Smo have also been detected in sporadic BCCs (Xie et al. 1998), and overexpression of Shh, Smo, Gli1, or Gli2 leads to BCCs in mice (Dahmane et al. 1997, Grachtchouk et al. 2000, 2003; Hutchin et al. 2005; Oro et al. 1997; Xie et al. 1998). Recently, Vidal et al. (2005) demonstrated that an HMG transcription box factor, Sox9, is also upregulated in BCC, and epistasis experiments suggest that Sox9 is downstream of the Shh signaling pathway in skin.

BCCs are thought to be derived from HFs, and consistent with this notion, Shh is expressed in the hair placodes of embryonic skin (St-Jacques et al. 1998) (). As revealed by Ptch expression, Shh is likely to signal in both the epithelial hair germ and its underlying mesenchymal condensate, suggesting its potential role in the epithelial-mesenchymal cross talk essential for follicle formation (Oro & Higgins 2003, Oro et al. 1997). Loss-of-function mutations in Shh are still permissive for hair germ formation, placing Shh genetically downstream of Wnt and Noggin signaling (). However, placodes fail to develop further, thus positioning Shh upstream from the proliferative cascade essential for HF morphogenesis (Chiang et al. 1999, St-Jacques et al. 1998, Wang et al. 2000). Mice deficient in Gli2 present a phenotype similar to Shh-null mice, suggesting that Shh acts mainly through Gli2 in HF (Mill et al. 2003).

Shh signaling is also important for follicle regeneration during the adult hair cycle. Although not expressed in the bulge, Shh is expressed in the matrix and in the developing germ, where it becomes polarized to one side during anagen progression (). The mechanisms underlying this exquisite restriction in expression are not understood, but Shh signaling is likely to span the matrix, as evidenced by Ptch expression (Gat et al. 1998, Oro & Higgins 2003). As would be predicted from the relative roles of Shh and Wnt signaling in embryonic skin, anti-Shh antibodies delivered to postnatal follicles block anagen progression (Wang et al. 2000), and similarly the Shh inhibitor cyclopamine blocks hair regeneration (Silva-Vargas et al. 2005). Conversely, Shh or small-molecule Shh agonists accelerate the progression from telogen to anagen (Paladini et al. 2005, Sato et al. 1999).

Whereas Shh plays a role in matrix cell proliferation in the hair cycle, Indian hedgehog (Ihh) is expressed in the sebaceous gland. Additionally, both human and mouse sebaceous tumors overexpress Ihh but not Shh. In normal sebaceous glands, Ihh is expressed in differentiating sebocytes, and nuclear Gli1 is present in sebocyte progenitors (Niemann et al. 2003). In vitro inhibition of hedgehog signaling inhibits growth and stimulates differentiation of sebocytes, suggesting a paracrine mechanism by which Ihh secreted by differentiated sebocytes stimulates proliferation of sebocyte precursors (Niemann et al. 2003). Transgenic overexpression of the other members of Shh family shows that Desert hedgehog is a functional homolog to Shh in the skin (Adolphe et al. 2004).

Bmps are secreted proteins that activate signal transduction by binding to a transmembrane receptor complex composed of Bmpr1a and Bmpr1b receptors. Upon ligand binding, Bmpr1b phosphorylates the cytoplasmic tail of Bmpr1a, which in turns phosphorylates the R-Smad DNA-binding protein (Smad 1, 5, and 8), which in turn complexes with one of its partner Smads (typically Smad 4) to translocate to the nucleus and mediate target gene expression (Shi & Massague 2003) ().

Bone morphogenetic protein (BMP) signaling pathway during hair follicle morphogenesis and differentiation. (a) Schematic of the BMP pathway. The extracellular availability of BMP proteins is tightly regulated by soluble BMP inhibitors such as Noggin. BMP dimers bind a heterodimeric receptor complex (BMPR-I and BMPR-II) that phosphorylates and activates R-Smad (Smads 1, 5, and 8), which then associates with its co-Smad (Smad 4) partner. Once activated, the R-Smad/co-Smad complex is translocated into the nucleus, where it transactivates its target genes. (b) Role of BMPs in hair follicle morphogenesis. BMP signals are transmitted to and from the overlying epidermis to underlying dermal condensates. Although the role these BMP signals play is not fully understood, this exchange of signaling is thought to play a role in the early specification of sites of hair follicle morphogenesis. As dermal condensates form, they express the BMP-inhibitor Noggin, which is required for normal follicle development and permissive for Lef1 expression and Wnt signaling. Later, as follicle maturation has progressed, the activation of BMP receptor signaling is essential for the matrix cells to differentiate to form the hair shaft and its inner root sheath (IRS) channel. BMP signaling also regulates epidermal proliferation in the skin. DP, dermal papilla.

Bmpr1a is expressed throughout most of the developing skin epithelium. The pattern of Bmp expression is particularly elaborate in the HF. In early skin development, Bmp2 is expressed in the placode epithelium, whereas Bmp4 is expressed by the underlying mesenchyme (Kratochwil et al. 1996; Lyons et al. 1989, 1990; Wilson et al. 1999). In adult HFs, Bmps also appear to function in epithelial-mesenchymal interactions. In the DP, Bmp4, -6, and -7 are expressed (Kratochwil et al. 1996; Lyons et al. 1989, 1990; Rendl et al. 2005; Wilson et al. 1999), although Bmp6 may also function in bulge SC quiescence and/or maintenance (Blanpain et al. 2004). In addition, Bmps are differentially expressed in the various lineages of the HF, with Bmp7 and -8 in the IRS and Bmp2 and -4 in the hair shaft precursors.

The role for Bmp signaling in skin development begins in the neuroepithelium, when Bmp signaling specifies uncommitted ectodermal cells to become epidermis (Nikaido et al. 1999). Once the embryonic skin SC progenitor cells have been specified, the next crossroads for signaling appears to be at the juncture of hair placode formation. In a process bearing a certain resemblance to the formation of the neural tube, placode formation is dependent on Noggin, a soluble inhibitor of Bmp signaling (Botchkarev et al. 1999, Jamora et al. 2003). Conditional ablation of the Bmpr1a gene also results in the accumulation of large masses of undifferentiated, Lef1-expressing, placode-like cells, further emphasizing a role for Bmp inhibition in the early stages of HF morphogenesis (Andl et al. 2004, Kobielak et al. 2003).

The conditional targeting of the Bmpr1a gene also revealed a positive role for Bmp signaling in the differentiation of matrix cells into IRS and hair shaft lineages (Andl et al. 2004, Kobielak et al. 2003, Ming Kwan et al. 2004, Yuhki et al. 2004). Several markers of matrix cell differentiation (FoxN1/nude, Hoxc13, Msx2, and GATA3) were strongly reduced or absent following the ablation of Bmpr1a. Notably and in striking contrast, Shh and Lef1 expression was expanded, as is also seen in transgenic mice expressing Noggin under the control of the Msx2 promoter (Kulessa et al. 2000). Nuclear -catenin was also decreased in the Bmpr1a-deficient matrix cells, demonstrating that Bmp signaling lies upstream of -catenin signaling during matrix cell differentiation. These findings strengthen the view that the inhibition of Bmp signaling is required for SC activation toward the HF cell fate, whereas Bmp signaling is required for the differentiation of activated SCs to adopt one or more of the six different lineages that compose the mature HF (Kobielak et al. 2003).

Several other lines of evidence suggest that the inhibition of Bmp signaling promotes SC activation. At the conclusion of the normal hair cycle, proliferation ceases and the HF enters the destructive phase (catagen). By contrast, Bmpr1a-null ORS continues to proliferate and grow downward, leading to an accumulation of matrix cells and the formation of follicular tumors (Andl et al. 2004, Ming Kwan et al. 2004). Conversely, treatment of cultivated bulge SCs with BMP6 inhibits their proliferation and leads to a transient withdrawal from the cell cycle (Blanpain et al. 2004, Botchkarev et al. 1999).

Similar to other major signaling pathways in skin, Notch signaling is involved in a variety of cell fate decisions across the animal kingdom. Transmembrane Notch receptors (Notch14 in mammals) bind transmembrane ligands, either Jaggeds (2) or deltas (3). Upon ligand engagement, membrane Notch receptors are sequentially cleaved, first by a metalloproteinase and then by -secretase, which releases the active Notch intracellular domain (NICD), freeing it to translocate to the nucleus and associate with the DNA-binding protein RBP-J. Upon NICD binding, RBP-J is converted from a transcriptional repressor to an activator, leading to the induction of downstream Notch target genes (Artavanis-Tsakonas et al. 1999) ().

Notch signaling pathway during epidermal stratification and hair follicle differentiation. (a) Schematic of canonical Notch signaling. Upon ligand (Jagged or Delta) binding, the Notch transmembrane receptor is cleaved by proteases (ADAM protease and -secretase), releasing the Notch intracellular domain (NICD), which can then translocate into the nucleus and associate with the DNA-binding protein RBP-Jk to permit transcription of target genes. (b) Role of Notch1 in skin development. Notch1 is cleaved and generates its active form, NICD1, which controls epidermal stratification and differentiation. Early, NICD1 is present in basal cells but later it is found primarily in suprabasal cells. Loss-of-function studies suggest that Notch1 acts as a tumor suppressor in skin epidermis to restrict proliferation to the basal layer. Notch1 also plays a role in the hair follicle, where it has been demonstrated to play a critical role in the differentiation of the inner root sheath and the hair shaft.

Multiple components of the Notch signaling pathway are expressed in embryonic and adult epidermis. During the early stage of epidermal stratification, Notch1 is expressed and active in the basal and suprabasal cells of the epidermis and sebaceous glands (Okuyama et al. 2004, Rangarajan et al. 2001) (). In the latter stages of epidermal stratification, Notch1 activity decreases in the basal layer and becomes more restricted to the spinous layer (K1-positive cells) (Okuyama et al. 2004). Loss of Notch1 function results in a defect of IFE differentiation (Rangarajan et al. 2001).

In the HF, Notch13 are expressed in proliferative matrix cells and in differentiating HF cells (Kopan & Weintraub 1993, Pan et al. 2004) (). When both Notch 1 and Notch2 or PS1 and PS2 genes involved in Notch processing are conditionally ablated in the matrix, HFs are quantitatively lost and epidermal cysts arise, underscoring the role for Notch signaling in follicle maturation and differentiation (Pan et al. 2004). The consequences of Notch1 deletion are most directly deleterious to the sebaceous glands, which are reduced in the single conditional knockout animals; in the absence of both Notch1 and Notch2, sebaceous glands are missing altogether (Pan et al. 2004). Conditional gene targeting of RBP-J also results in hair loss and epidermal cyst formation (Yamamoto et al. 2003).

Related to the natural role of Notch signaling in skin, loss of Notch 1 potentiates skin tumor development upon chemically induced carcinogenesis (Nicolas et al. 2003). Conversely, NICD overexpression in cultured cells inhibits keratinocyte proliferation, in part by upregulating the p21 target gene, which possesses a functional RBP-J-binding site within its promoter (Rangarajan et al. 2001). Although these studies point to a role for Notch in hair differentiation and inhibition of proliferation, sustained activation of Notch signaling through NICD1 overexpression in hair shaft progenitors unexpectedly promotes matrix cell proliferation and impairs hair shaft differentiation (Lin & Kopan 2003, Lin et al. 2000). These findings raise the possibility that the roles for Notch signaling in the epidermis and HF may be distinct.

Further insights into Notch signaling in the skin come from studies on chicken feather formation. As in mice, Notch1 is expressed in chick epidermal placode, and delta is expressed in the underlying mesenchyme. Delta overexpression in a small epidermal patch leads to an acceleration of feather development, whereas massive overexpression in the epidermis leads to a decrease in feather development (Crowe et al. 1998). These findings suggest a model in which Notch signaling promotes HF development in the preexisting placode but restricts neighboring cells from adopting a similar fate. The generalization of this model for other appendage development in other species requires further investigation, but the model mirrors that of Notch signaling in epidermal and neural fate specification in Drosophila.

Although loss of Notch1 in the epidermis does not impair early follicle morphogenesis, it does progressively reduce the number of HFs over time (Vauclair et al. 2005). It is still unclear what the downstream genes regulated by Notch signaling in the epidermis are, and how these genes mediate their cellular function. It also remains to be determined how Notch signaling acts in the bulge SC niche, how Notch regulates hair cycle, and how the Notch signaling pathway is connected to the other signaling pathways known to influence SC maintenance and activation.

The ends of chromosomes are called telomeres, and they consist of short, tandem DNA sequence repeats that associate with specific proteins and protect chromosome ends from degradation and recombination. Telomerase is a reverse transcriptase that synthesizes the DNA repeats to circumvent telomere shortening during DNA replication. Telomerase reverse transcriptase (TERT) is the catalytic subunit of the protein complex that makes the telomerase. Telomerase is upregulated in many human cancers, and TERT cooperates with other oncogenes to transform normal cells into tumor cells (Blackburn 2001).

TERT has been postulated to extend the proliferative potential of cells, and hence it has been speculated to play a role in SC biology. When the K5 promoter is used to drive TERT overexpression in the basal epidermal layer of transgenic mice, animals are more susceptible to skin tumorigenesis when exposed to chemical carcinogens, and they repair their wounds more rapidly (Gonzalez-Suarez et al. 2001). Conversely, mice deficient for TERC, another key component of telomerase, are resistant to skin chemical carcinogenesis (Gonzalez-Suarez et al. 2000).

In bulge SCs, increased TERT activity results in proliferation and premature entry into the anagen stage (Flores et al. 2005, Sarin et al. 2005). Flores et al. (2005) assumed that the reduced epidermal proliferation seen in TERC-null mice reflected the importance of telomerase and telomere length in bulge SC behavior. In contrast, Sarin et al. (2005) discovered surprisingly that TERC affects the skin in a fashion independent of its role in telomerase function and telomere length. Both groups have posited that TERT and TERC exert their function on the quiescent SCs within the bulge. However, given the need to sustain proliferation in the matrix cells during the growth phase of the hair cycle, it seems more plausible that a need for enhancing conventional telomerase activity would be felt by the proliferating matrix compartment rather than the infrequently cycling cells of the bulge. Additional studies are needed to clarify these conflicting results and determine the mechanism by which telomerase overexpression allows or facilitates skin carcinogenesis and SC activation.

Bulge SCs display elevated levels of several cytoskeleton-related genes known to be regulated by small G proteins of the Rho family of small GTPases. Rac is a pleiotropic regulator of actin dynamics, intercellular adhesion, and cell migration, and as such, it is expressed broadly in proliferating cells. Conditional ablation of the Rac1 gene in the proliferating keratinocytes of skin rapidly depletes the proliferative compartments, leading to a mobilization and depletion of SCs (Benitah et al. 2005).

A priori, a similar outcome might be expected for the depletion of many different types of essential epidermal genes. However, Rac1 was of particular intrigue to Watt and her colleagues (Arnold & Watt 2001, Braun et al. 2003, Frye et al. 2003, Waikel et al. 2001) because it is a negative regulator of c-Myc, whose elevated expression has been reported to deplete the population of bulge LRCs. It will be interesting in the future to see the extent to which, as posited by the authors, Rac1 may act at the nexus of the transition between the SC and its committed progeny (Benitah et al. 2005).

Given the general consensus that overexpression of c-Myc depletes bulge SCs and drives them to differentiate along the epidermal lineage (Arnold & Watt 2001, Braun et al. 2003, Frye et al. 2003, Waikel et al. 2001), it came as a surprise that conditional loss of endogenous c-Myc also leads to a loss of bulge LRCs and precocious differentiation of basal epidermal cells (Zanet et al. 2005). Although the jury is still out, one possible explanation for the seemingly disparate results between gain and loss of c-Myc function is that c-Myc acts at multiple points along the bulge SC lineages, and a perturbation at one or more of these steps may indirectly impact the behavior of SCs. Consistent with this notion is that both gain- and loss-of-function studies point to a role for c-Myc in governing the sebaceous gland lineage, which is also thought to rely on bulge SCs.

The skin epithelium is a complex tissue containing three distinct lineages that form the IFE, the HF, and the sebaceous gland.

The IFE constantly self-renews to provide a new protective layer at the skin surface, and HFs undergo a perpetual cycle of growth and degeneration to ensure the renewal of the hair pelage.

Different populations of progenitor cells contribute to lineage homeostasis, but to date, only bulge SCs have been demonstrated clonally to be multipotent with the ability to differentiate into all three differentiation lineages.

Bulge SCs can be activated and mobilized, at each cycle of hair follicle regeneration and after wound healing, to provide cells for tissue repair.

Recent progress in the isolation and molecular characterization of bulge SCs has provided new insights into the various mechanisms implicated in SC maintenance and activation.

Conserved signaling pathways regulating developmental decisions throughout the animal kingdom are reutilized during adult life to regulate the functions of skin epithelial SCs, and deregulation of these signaling pathways leads to the development of cancer in various tissues.

In this review, we try to highlight some of the significant advances made recently in skin stem cell biology, and we place them within the context of the historical foundations that made this current research possible. In closing, we offer a few of the unanswered questions in the field of skin stem cells that we think are likely to capture the attention of skin biologists in the years to come.

Do common molecular mechanisms govern the fundamental characteristics shared by adult skin SCs and other SCs, namely self-renewal and maintenance of the undifferentiated state? Comparisons of the transcriptional profiles of different types of SCs isolated directly from their respective tissues should help to identify possible candidates, as will the profiling of SCs residing in and out of their niches, and in quiescent and activated states. As candidate genes are identified, functional analyses of putative self-renewal or differentiation inhibitory SC genes in skin should reveal their importance and begin to unravel the pathways involved.

What is the mechanism by which quiescent bulge SCs are activated? Little is known about the signals needed to mobilize bulge SCs to reepithelialize epidermal wounds and to replenish the sebaceous gland. Even for the better understood process of SC activation during the hair cycle, a number of key issues remain unsolved. At the crux of the problem is whether follicle SC activation involves an intrinsic clock mechanism and/or whether it involves a signal from the DP. Although a change in the status of Lef1/Tcf/-catenin-regulated genes has been implicated in follicle SC activation, it is still not clear where a Wnt signal is involved, where it comes from, how the pathway exerts its effects, how it converges with other key signaling pathways, and how the program of gene expression is established that leads to follicle formation.

What is the relationship between the bulge SCs and the proliferative compartments of the epidermis, sebaceous gland, and HF? Do proliferating skin keratinocytes retain unipotent or even multipotent SC properties, or are they committed to embark on a terminal differentiation program? The point of no return in the skin SC field is an important one. Lineage-tracing experiments and the recent studies on asymmetric cell divisions in the skin provide new insights into these issues, but additional studies are now needed to illuminate the molecular relations between these different proliferative populations within the skin.

What is the relationship between the multipotent progenitors of embryonic skin epidermis and the multipotent SCs of the bulge? Embryonic skin effectively begins as a single layer of multipotent progenitors, but they differ from bulge SCs in their proliferative status and their lack of an apparent niche. Are bulge SCs simple quiescent counterparts of their embryonic brethren, or are there intrinsic differences between them? As methods are honed to isolate and characterize the early embryonic SCs, this relationship should become clearer. Additionally, it will be helpful to trace the development of the bulge from its early origins to its site in the postnatal follicle.

Are SCs at the root of cancers in the skin? Cancer is the result of a multistep process requiring the accumulation of mutations in several genes. For most cancers, the target cells of oncogenic mutations are unknown. Adult SCs may be the initial target cells, as they self-renew for extended periods of time, providing increased opportunity to accumulate the mutations required for cancer formation. Certain cancers contain cells with SC characteristics with high self-renewal capacities and the ability to re-form the parental tumor on transplantation. However, whether the initial oncogenic mutations arise in normal SCs or in more differentiated cells that reacquire SC-like properties remains to be determined. The demonstrations that SCs are the target cells of the initial transforming events and that cancers contain cells with SC characteristics await the development of tools allowing for the isolation and characterization of normal adult SCs. For most epithelia in which cancer arises, such isolation techniques are not available. The new methods to isolate and specifically mark skin SCs make it now possible to test experimentally the cancer SC hypothesis in the skin.

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Epidermal Stem Cells of the Skin - PubMed Central (PMC)

Skin Stem Cells Comments Off on Epidermal Stem Cells of the Skin – PubMed Central (PMC) | April 16th, 2020

Medical skin care products are used for beautifying or to address some other skin care problems. The cosmetic industry is booming and skin care forms a very huge part of this industry. The aesthetic appearance is so important that people spend a lot on skin care products and treatment. People being more technologically aware of the various new skin care products trending in the market. In addition to the aesthetic application, the medical skin care products are also used to address issues such as acne, pimples or scars.

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Medical Skin Care Products Market: Drivers and Restraints

The medical skin care products is primarily driven by the need of natural based active ingredients products which are now trending in the market. Consumers demand medical skin care products which favor health and environment. Moreover, the consumers are updated with the trends so that various companies end up providing such products to satisfy the customers. For instance, a single product face mask has thousands of different variants. This offers consumers different options to select the product depending on the skin type. Moreover, the market players catering to the medical skin care products are offering products with advanced technologies. For instance, Santinov launched the CICABEL mask using stem cell material based on advanced technologies. The stem cells used in the skin care product helps to to protect and activate the cells and promote the proliferation of skin epidermal cells and the anagenesis of skin fibrosis.

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On the basis of product type the medical skin care products market can be segmented as:

On the basis of application, the medical skin care products market can be segment as:

On the basis of distribution channel, the medical skin care products market can be segment as:

Medical Skin Care Products Market: Overview

Medical skin care products are used to address basic skin problems ranging from acne to scars. There are various advancements in the ingredients used to offer skin care products to the consumers. For instance, the use of hyaluronic acid and retinoids is the latest development in the industry. The anti-aging creams are at the forefront as the help treating issues such as wrinkles, scars, acne, and sun damage. Another, product in demand is the probiotic skincare which include lactobacillus and bifidobacterium.

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Medical Skin Care Products Market: Region-wise Outlook

In terms of geography, medical skin care products market has been divided into five regions including North- America, Asia- Pacific, Middle-East & Africa, Latin America and Europe. North America dominated the global medical skin care products market as international players are acquiring domestic companies to make their hold strong in the U.S. LOral is accelerating its U.S. market by signing a definitive agreement with Valeant Pharmaceuticals International Inc. to acquire CeraVe, AcneFree and Ambi skin-care brands for US$ 1.3 billion. The acquisition is expected LOreal to get hold of the brands in the price-accessible segment. Asia Pacific is expected to be the fastest growing region owing to the increasing disposable income and rising awareness towards the skin care products.

Medical Skin Care Products Market: Key Market Participants

Some of the medical skin care products market participants are ,

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Medical Skin Care Products Market Structure and Its Segmentation for the Forecast 2017 2025 - Curious Desk

Skin Stem Cells Comments Off on Medical Skin Care Products Market Structure and Its Segmentation for the Forecast 2017 2025 – Curious Desk | April 16th, 2020

Researchers at Lund University in Sweden have succeeded in restoring mobility and sensation of touch in stroke-afflicted rats by reprogramming human skin cells to become nerve cells, which were then transplanted into the rats' brains. The study has now been published in the Proceedings of the National Academy of Sciences (PNAS).

"Six months after the transplantation, we could see how the new cells had repaired the damage that a stroke had caused in the rats' brains," says Professor Zaal Kokaia, who together with senior professor Olle Lindvall and researcher Sara Palma-Tortosa at the Division of Neurology is behind the study.

Several previous studies from the Lund team and others have shown that it is possible to transplant nerve cells derived from human stem cells or from reprogrammed cells into brains of rats afflicted by stroke. However, it was not known whether the transplanted cells can form connections correctly in the rat brain in a way that restores normal movement and feeling.

"We have used tracking techniques, electron microscopy and other methods, such as light to switch off activity in the transplanted cells, as a way to show that they really have connected correctly in the damaged nerve circuits. We have been able to see that the fibres from the transplanted cells have grown to the other side of the brain, the side where we did not transplant any cells, and created connections. No previous study has shown this," says Zaal Kokaia, who, even though he and colleague Olle Lindvall have studied the brain for several decades, is surprised by the results.

"It is remarkable to find that it is actually possible to repair a stroke-damaged brain and recreate nerve connections that have been lost. The study kindles hope that in the future it could be possible to replace dead nerve cells with new healthy nerve cells also in stroke patients, even though there is a long way to go before achieving that," says Olle Lindvall.

The researchers have used human skin cells that have been reprogrammed in the laboratory to become nerve cells. They were then transplanted into the cerebral cortex of rats, in the part of the brain that is most often damaged after a stroke. Now the researchers will undertake further studies.

"We want to know more about how the transplanted cells affect the opposite hemisphere of the brain. We also want to take a closer look at how a transplant affects intellectual functions such as memory. In addition, we will study possible side effects. Safety is, of course, extremely important for cell transplantation if it is going to be used clinically in the future," says Zaal Kokaia.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Researchers Have Succeeded in Restoring Mobility and Sensation of Touch in Stroke-Afflicted Rats - Technology Networks

Skin Stem Cells Comments Off on Researchers Have Succeeded in Restoring Mobility and Sensation of Touch in Stroke-Afflicted Rats – Technology Networks | April 15th, 2020

captionStress may cause gray hair prematurely.sourceManop_Phimsit/Shutterstock

Stress can affect the body in many different ways. And while it seems that stressful life events like being president may cause gray hair, the truth is a bit more complicated.

Gray hair is likely caused by a combination of genetics, aging, and hormones, and there is some research to suggest that stress can turn hair gray prematurely. Heres what you need to know.

When youre born, your hair color is determined by natural pigments in your skin called melanin.

Human hair follicles contain two types of melanin: eumelanin and pheomelanin, says Leann Poston, MD, a licensed physician. The wide diversity of possible hair colors comes from the production ratio of these two types of melanin.

Melanin is created from melanocytes, which are the cells found in your skin and hair follicles. When melanocytes stop producing melanin, your hair color changes to gray.

Melanocytes often stop producing melanin as you age, which is why gray hair is so common among the elderly. However, its common for hair to start turning gray around age 35.

Overall, Poston says that a combination of factors such as genetics, hormones, and your environment will determine exactly when your hair turns gray.

Though stress alone will not cause gray hair, there is some research that suggests it may speed up the graying process.

For example, a 2020 study published by the journal Nature found that when mice were exposed to stress, they lost melanocyte cells and gained gray hair as a result.

This is an interesting study that links stress to an abnormal conversion of stem cells to a more differentiated form, melanocytes, Poston says.

Melanocyte stem cells typically decrease in numbers as you age. But premature activation, associated with increases in a stress hormone called norepinephrine (or noradrenaline), actually caused these cells to decline more quickly in mice leading to the gray hair that researchers observed.

Poston says she doesnt believe this animal study is enough to definitively say that the same is true for humans. But other research has also suggested that stress can accelerate graying.

For example, a 2018 study in the International Journal of Trichology observed an increase in oxidative stress as a result of psychological stress and higher levels of oxidative stress, which contributes to a complicated biological imbalance in humans, are associated with an increased risk of many chronic diseases as well as premature aging.

The study suggests that premature gray hair, or the graying of hair by age 20, is linked with higher levels of oxidative stress, which may increase with more of your everyday psychological stressors like a difficult job or the pressure to provide for your family.

In addition, cigarette smoking and vitamin deficiencies which can also increase oxidative stress have been associated with early graying.

Overall, genetics and aging are likely to be more determinate for when your hair turns gray. But, as some research has suggested, psychological stress and other unhealthy risk factors may accelerate this graying process.

Read more:
Does stress cause gray hair? It may lead to premature graying - Business Insider

Skin Stem Cells Comments Off on Does stress cause gray hair? It may lead to premature graying – Business Insider | April 14th, 2020

Stress can affect the body in many different ways. And while it seems that stressful life events like being president may cause gray hair, the truth is a bit more complicated.

Gray hair is likely caused by a combination of genetics, aging, and hormones, and there is some research to suggest that stress can turn hair gray prematurely. Here's what you need to know.

When you're born, your hair color is determined by natural pigments in your skin called melanin.

"Human hair follicles contain two types of melanin: eumelanin and pheomelanin," says Leann Poston, MD, a licensed physician. "The wide diversity of possible hair colors comes from the production ratio of these two types of melanin."

Melanin is created from melanocytes, which are the cells found in your skin and hair follicles. When melanocytes stop producing melanin, your hair color changes to gray.

Melanocytes often stop producing melanin as you age, which is why gray hair is so common among the elderly. However, it's common for hair to start turning gray around age 35.

Overall, Poston says that a combination of factors such as genetics, hormones, and your environment will determine exactly when your hair turns gray.

Though stress alone will not cause gray hair, there is some research that suggests it may speed up the graying process.

For example, a 2020 study published by the journal Nature found that when mice were exposed to stress, they lost melanocyte cells and gained gray hair as a result.

"This is an interesting study that links stress to an abnormal conversion of stem cells to a more differentiated form, melanocytes," Poston says.

Melanocyte stem cells typically decrease in numbers as you age. But premature activation, associated with increases in a stress hormone called norepinephrine (or noradrenaline), actually caused these cells to decline more quickly in mice leading to the gray hair that researchers observed.

Poston says she doesn't believe this animal study is enough to definitively say that the same is true for humans. But other research has also suggested that stress can accelerate graying.

For example, a 2018 study in the International Journal of Trichology observed an increase in oxidative stress as a result of psychological stress and higher levels of oxidative stress, which contributes to a complicated biological imbalance in humans, are associated with an increased risk of many chronic diseases as well as premature aging.

The study suggests that premature gray hair, or the graying of hair by age 20, is linked with higher levels of oxidative stress, which may increase with more of your everyday psychological stressors like a difficult job or the pressure to provide for your family.

In addition, cigarette smoking and vitamin deficiencies which can also increase oxidative stress have been associated with early graying.

Overall, genetics and aging are likely to be more determinate for when your hair turns gray. But, as some research has suggested, psychological stress and other unhealthy risk factors may accelerate this graying process.

View original post here:
Does stress cause gray hair? It may lead to premature graying - Insider - INSIDER

Skin Stem Cells Comments Off on Does stress cause gray hair? It may lead to premature graying – Insider – INSIDER | April 13th, 2020

Theres no doubt that as we get older, our skin's wants and needs begin to change. Whileskincare routines of our late teens andearly twenties might have focused heavily on oil-absorbing products that worked to keepbreakouts in check, as we enter our thirties, its likely that other, more pressingskin issues start cropping up. For instance, spots of pigmentation might start surfacing, fine lines may begin to form and skin that was once plump andglowing could appear lacklustre and dull.

The sorry truth is that as we enter our thirties, all of the stuff that makes our skin naturally healthy starts to deteriorate. By the time we get to our thirties, we have around 50% collagen left in our skin.Hyaluronic acid production also slows down and cellular turnover only hits us around every four to six weeks. Everything starts to slow down, says celebrity facialist, Michaella Bolder.

So what exactly does all of this mean? And how can we help minimise the affects of ageing on our skin? To help decode everything there is to know about caring for skin in your thirties, I caught up with some of the top skincare experts in the business. Unsurprisingly, I found that, for the most part, they all preached the same message: As we make our way into our thirties, certainingredients simply cannot be compromised on.

Keeping scrolling for the six products they seriously recommend and to shop the best formulas out there.

As we enter our thirties, its understandable to assume that well start experiencing less breakouts as natural oil production starts to decline. However, thats not to say that regularexfoliation isnt necessary anymore.

Just because breakouts are most associated with teenage years, acne can still occur well into our thirties. In my clinical practice I frequently see patients in their thirties with adult onset acne, says Dr Catherine Borysiewicz, Consultant Dermatologist at the Cadogan Clinic. Data suggests women are more frequently affected by adult acne compared with men. The exact reason for this is unknown, but felt to be related to fluctuating hormone levels: during periods or from birth control pills, and also during and following pregnancy. The role of stress is also becoming more apparent, she warns.

Not only do regular acid treatments encourage cell turnover (something that starts slowing down in our thirties), they can also help to exfoliate for a clearer, more radiant complexion. Just remember, only exfoliate once or twice a week and always follow up with SPF.

REN Clean Skincare Ready Steady Glow Daily AHA Tonic (27)

Medik8 Blemish Control Pads (26)

Paula's Choice Resist Advanced Smoothing Treatment 10% AHA (37)

This Works Morning Expert Multi-Acid Pads (33)

Weve heard it time and time again, but its true that no skincare routine is complete without some sort ofvitamin C product, especially if youre in your thirties. But what exactly is it, and what does it do? To start with, vitamin C is a very powerful antioxidant that works against skin-damaging free radicals such as pollution and UV. And unfortunately, by the time we reach our thirties, the effects of free radical damage start to become more and more evident. Vitamin C eradicates free radicals that have hidden within our skin cells that start to diminish our healthy cells, turning them into unhealthy, broken ones. It basically eats free radicals up like Pacman, says Bolder.

On top of that, vitamin C is great for treating pigmentation and lightening dark spots without altering normal skin tone. Leading aesthetic doctor and surgeon,Dr Mayoni also warns, In our thirties, pigment cells can start to become overactive and so the skin starts to look less plump, less hydrated and with more areas of pigmentation appearing.

Drunk Elephant C-Firma Day Serum (67)

Kiehl's Powerful-Strength Line-Reducing Concentrate (52)

La Roche-Posay Pure Vitamin C10 Serum (38)

SkinCeuticals C E Ferulic Serum (140)

As a rule, it tends to be that the older we get, the more potent and active our skincare needs to be. However, there is one particular product that we can never have too much of. Although it sounds scary, hyaluronic acid isnt actually an acid in the way that you might think. Whereas most acids work to exfoliate, hyaluronic acid is a powerful moisture-binder that occurs naturally in our skin.

What is a moisture-binder, I hear you ask? Able to retain up to x1000 its own weight in water, hyaluronic acid is able to hold onto any moisture and hydration in order to keep skin looking plump and supple. The bad news is that as we enter our thirties, our hyaluronic acid supplies start declining. Upon reaching our thirties, our natural stores of hyaluronic acid decrease, warns Rowan Hall-Farrise, Head of Global Education at QMS Medicosmetics. Not only does the amount that our skin naturally produces start to diminish, but years of exposure to free radicals also begins to wear our existing supplies down, hence why vitamin C is important. Are you keeping up?

Using a hyaluronic acid serum twice a day is essential and be sure to apply it 10 minutes before you use any retinol, advises Bolder.

Zelens Z Hyaluron Hyaluronic Acid Complex Serum Drops (55)

The INKEY List Hyaluronic Acid Serum (6)

Vichy Mineral 89 (25)

Eucerin Hyaluron-Filler Ultra Light Moisture Booster Gel-Cream (25)

Collagen might just be one of the most-mentioned words in beauty advertising, but its actually quite a complex thing. A naturally-occurring protein, collagen is the stuff that really helps hold everything together and support the skin, making it healthy, plump and bouncy. Just like hyaluronic acid, free radicals and ageing start to impact our collagen production as we get into our thirties. From the age of 25, our collagen production starts to decrease. Our late twenties and early thirties is when we should start incorporating collagen treatments into our regimens, says Hall-Farrise.

However, despite what beauty brands might tell you, supplementing collagen isn't as easy as slapping on a collagen-infused face cream - the molecules are far too big to be absorbed by the skin. Luckily, there are ways to encourage the bodys natural collagen production, but were warning you that they dont come cheap. The professional treatment of microneedling helps to stimulate collagen, but you can also use stem cell products at home. The stem cells are there to encourage collagen stimulation and preserve the collagen that we have left in our skin, says Bolder.

If you can't justify the expense, don't worry too much, keeping on top of your hyaluronic acid serums twice a day should be enough to keep skin looking plump and firm in the short term.

Augustinus Bader The Cream (205)

QMS Medicosmetics Collagen System Sensitive (199)

Sarah Chapman Skinesis Stem Cell Collagen Activator Duo (149)

Indie Lee Stem Cell Serum (127)

You knew this was coming, right? While its all too easy to switch off the minute you hear the word retinol (seriously, do we ever stop talking about it?), experts warn that now is actually the time to start paying attention. In fact, Bolder actually advises against using retinol any time before your mid-thirties. Retinol should not be in your early thirties, but in your mid to late thirties I recommend starting to use a retinol at around 1%, she says.

If youre totally out of the loop with exactly what retinol does and why its beautys ingredient du jour, let me explain. A form of vitamin A (dont be fooled by the word vitamin, this stuff is seriously powerful), retinol increases cell turnover and is thought to be one of the only skincare ingredients that can actually help reverse the signs of ageing. Dr Laura Hamilton, aesthetic doctor and founder ofVictor & Garth explains, Retinol can really do wonders for your skin. It can improve skin texture, reduce pore size and minimise the appearance of fine lines and wrinkles. In our thirties, most of us will see results with retinol.

But be warned, its not always fun and games. Side effects of redness and peeling can take some getting used to, so start with a lower strength twice a week at night time only and build up, says Dr Hamilton.

La Roche-Posay Retinol B3 Serum (39)

Sunday Riley A+ High-Dose Retinoid Serum (70)

Origins Plantscription Overnight Moisturiser (49)

Elizabeth Arden Retinol Ceramide Line Erasing Night Serum Capsules X 30 (38)

Sure, the importance of SPF application might not be specific to any one decade of your life, but its crucial to reiterate that it should always feature in your daily skincare routine if you want to protect your skin from sun damage and ageing. While daily sun cream application might have been considered a more preventative measure in your twenties, in your thirties you might be starting to notice the physical damage that prolonged sun exposure can cause. Sun damage starts to come through in your thirties. So while vitamin C and retinol are needed to help reduce the damage already caused, SPF every single day will help prevent any further sun damage, says Bolder.

The Body Shop Skin Defence Multi-Protection Lotion SPF 50+ (18)

Institut Esthederm Adaptasun Sensitive Skin Face Cream Strong Sun (30)

Medik8 Advanced Day Total Protect (55)

Shiseido Expert Sun Ageing Protection Lotion SPF30 (35)

Next up, I've done my research, and these are the best anti-ageing products.

This article originally appeared on Who What Wear

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The 6 Skin Products Experts Say Every 30-Something Should Have in Their Routine - Yahoo Style

Skin Stem Cells Comments Off on The 6 Skin Products Experts Say Every 30-Something Should Have in Their Routine – Yahoo Style | April 13th, 2020

People who develop Parkinson's disease at a younger age (before age 50) may have malfunctioning brain cells at birth, according to a study that also identified a drug that may help these patients.

At least 500 000 people in the United States are diagnosed with Parkinson's each year. Most are 60 or older at diagnosis, but about 10% are between 21 and 50.

Parkinson's is a neurological disease that occurs when brain neurons that make dopamine become impaired or die. Dopamine helps coordinate muscle movement.

Symptoms get worse over time and include slow gait, rigidity, tremors and loss of balance. There is currently no cure.

"Young-onset Parkinson's is especially heart-breaking because it strikes people at the prime of life," said study co-author Dr Michele Tagliati, director of the Movement Disorders Program at Cedars-Sinai Medical Center in Los Angeles.

"This exciting new research provides hope that one day we may be able to detect and take early action to prevent this disease in at-risk individuals," he said in a hospital news release.

For the study, Tagliati and colleagues generated special stem cells from the cells of patients with young-onset Parkinson's disease. These stem cells can produce any cell type of the human body. Researchers used them to produce dopamine neurons from each patient and analysed those neurons in the lab.

The dopamine neurons showed two key abnormalities: build-up of a protein called alpha-synuclein, which occurs in most forms of Parkinson's disease; and malfunctioning lysosomes, structures that act as "trash cans" for the cell to break down and dispose of proteins. This malfunction could result in a build-up of alpha-synuclein, the researchers said.

"Our technique gave us a window back in time to see how well the dopamine neurons might have functioned from the very start of a patient's life," said senior author Clive Svendsen, director of the Cedars Sinai Board of Governors Regenerative Medicine Institute.

"What we are seeing using this new model are the very first signs of young-onset Parkinson's," Svendsen said in the release. "It appears that dopamine neurons in these individuals may continue to mishandle alpha-synuclein over a period of 20 or 30 years, causing Parkinson's symptoms to emerge."

The study was published in the journal Nature Medicine.

The researchers also tested drugs that might reverse the neuron abnormalities. A drug called PEP005 already approved by the US Food and Drug Administration for treating pre-cancers of the skin reduced elevated levels of alpha-synuclein both in mice and in dopamine neurons in the lab.

The investigators plan to determine how PEP005, which is available in gel form, might be delivered to the brain to potentially treat or prevent young-onset Parkinson's.

They also want to find out whether the abnormalities in neurons of young-onset Parkinson's patients also exist in other forms of Parkinson's.

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Young-onset Parkinson's may start in the womb - Health24

Skin Stem Cells Comments Off on Young-onset Parkinson’s may start in the womb – Health24 | April 12th, 2020

By Jessica Lake

Updated April 12, 2020 08:32:52

Almost two years ago, our world fell apart.

Our cheeky and sweet three-year-old son Larry suddenly became unwell. His previously robust physicality waned. His ruddy complexion became creamy.

His rosy cheeks and rose red lips glowed a pale pink at best. There were bad bruises on his legs darker and deeper ones than those dotting the knees of his identical twin brother. There was a strange patch of little red dots on his neck petechia, we would later learn pin-prick bleeding under the skin.

We took him to our GP. Then we took him to Monash Children's Emergency. Then, a few weeks later, we arrived at the Children's Cancer Centre of the Royal Children's Hospital.

He was diagnosed with idiopathic very severe aplastic anaemia. For unexplained reasons, his bone marrow had spontaneously started shutting down. We were disoriented and devastated.

Without the ability to make blood, Larry required constant transfusions. Every six-to-10 days, when his nose oozed or a blood blister appeared in his mouth, we would race to the clinic or emergency department (sometimes via ambulance) for a bag of platelets: "yellow medicine" our son called it. Once he could clot again we could relax a little.

About every one-to-three weeks, when he struggled to pull himself out of bed or off the couch, when his appetite diminished and his pallor grew too pale, he would receive a bag of "red medicine" to resuscitate his system.

Until mid 2018, I had the privilege and luck of never thinking much about blood donation. But now, the prospect of a shortage terrifies me.

Due to COVID-19, the Australian Red Cross Lifeblood service faces a critical shortage unless thousands of people donate.

Over a period of 14 months, while our son battled bravely through immunosuppressive treatment and multiple infections, he underwent more than 70 platelet transfusions and 40 blood transfusions. The blood of more than 100 kind souls kept him going.

One day last April, Larry's haemoglobin was the lowest it had ever been. In the 50s. Less than half the level of a "normal" person.

It was a Saturday morning, and I'd just raced him through city traffic to the hospital emergency department yet again.

Once we arrived, they ordered a bag of red cells. He dozed on the trolley bed. His lips the same colour as his skin. His skin the same colour as the sheet he had just vomited on.

I fidgeted and hopped back and forth around the doorway of our cubicle watching for the blood bank delivery. Please. Please. Please. An agonising wait. Finally, it arrived.

A rush of immense gratitude. The nurses did their double cross checks. Name, date of birth, patient number. Then it was hooked up to the IV Pump and connected. 235 millilitres over four hours.

I stared at the bag: "Collected 15 April 2019, due to expire 15 May 2019". I wondered who donated it on that Monday two weeks before. A man or a woman? Young or old? Which centre had they attended? Had they congratulated or rewarded themselves for their gift? I hoped so.

After 20 minutes, my dear little boy started to stir. He'd only had 19ml by then but it was already making a difference. A dusky warm colour was creeping into his complexion. Energy was reaching his cells again. By the time one hour had passed, he was sitting up, demanding food, drawing, playing I-spy and cracking jokes.

I assume if everyone could witness this miraculous transformation, we would all run to the blood bank and offer up our veins. By the end of the day, the bag of blood was empty and Larry was full of life again temporarily.

In August 2019, our son underwent a long-awaited bone marrow transplant.

From a pool of more than 30 million bone marrow donors worldwide, only three were a match, all from overseas.

Someone in Europe willingly, with no financial incentive or reward, booked into their local hospital and had stem cells sucked from their hip bones so that a stranger our son might live. An amazing act of generosity.

The sludgy burgundy bag arrived in Melbourne late at night on a commercial flight. Our little Larry had already undergone seven days of heavy chemotherapy in order to be ready to receive the cells. The last scraps of his immune system had been destroyed to make necessary space.

It was either the beginning, or the end of the road.

After a couple of months in isolation, Larry was discharged from hospital. A new beginning.

He is now six months post-transplant and doing well. He plays riotously with his twin brother and big sister. He no longer needs blood. He can make his own again, for now.

But many children at the Children's Cancer Centre cannot. They rely on platelets, plasma and blood to survive day-to-day. A shortage spells disaster.

Many are also relying on a bone marrow transplant for an ultimate cure. And due to travel bans and overwhelmed hospital systems globally, overseas bone marrow donors are now inaccessible indefinitely.

It is painful to imagine Larry's plight if the coronavirus occurred a year earlier.

Let's honour the tremendous courage of kids like Larry by showing ours. Make an appointment at Australia Red Cross Lifeblood today.

Give blood. Give your name to the bone marrow register. Give laughter, hope and life to these incredible kids.

Let's not let cancer treatment become another casualty of the coronavirus crisis.

Jessica Lake is a mother, writer, academic, and member of the Parent's Advisory Group of the Children's Cancer Centre at the Royal Children's Hospital, Melbourne.

Topics:covid-19,diseases-and-disorders,health,blood,children,family-and-children,community-and-society,melbourne-3000,australia

First posted April 12, 2020 05:00:59

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My son needed regular blood transfusions, but now coronavirus threatens the survival of children like him - ABC News

Skin Stem Cells Comments Off on My son needed regular blood transfusions, but now coronavirus threatens the survival of children like him – ABC News | April 12th, 2020

A.I.has already gotten to almost sci-fi levels of emulating brain activity, so much so that amputees can experience mind-controlled robotic arms, and neural networks might soon be a thing. That still wasnt enough for the brains behind one ambitious startup, though.

Cortical Labs sounds like it could have been pulled from the future. Co-founder and CEO Hong Wen Chong and his team are merging biology and technology by embedding real neurons onto a specialized computer chip. Instead of being programmed to act like a human brain, it will use those neurons to think and learn and function on its own. The hybrid chips will save tremendous amounts of energy with an actual neuron doing the processing for them.

Biological neural networks can solve problems in unfamiliar situations independent of acquired knowledge due to their self-organizing properties, says the companys website. Fluid intelligence is an essential requirement for autonomous robots.

Bio-computing was first switched on with neurons from mouse embryos, but can now use human neurons. Cortical Labs can morph human skin cells back into stem cells and then induce them to grow into actual human neurons. This was a process originally developed by Japanese scientists who were looking to eliminate the controversy that comes with using human embryonic stem cells. These cells are so useful because they havent yet decided what their function will be. That means they can be manipulated into just about anything.

After the skin cells undergo their transformation into neurons, a nourishing liquid medium is used to embed them onto a tiny metal oxide chip that has an even tinier grid of 22,00 electrodes. It is these electrodes that speak to programmers about when to zap electrical inputs to the neurons, letting them know what kind of outputs they are getting.

Artificially created neurons turn out the same as neurons that would (hypothetically) be taken from your gray matter, except there is no brain invasion required. Something like that would cross over from science fiction to science horror.

Right now, these chips are close to processing things like a dragonfly brain, so there are still upgrades to be made. Remember spending hours at the arcade playing Pong? Chong is determined to teach the chips to play that retro Atari game, and being powered by neurons uses just a fraction of what they would if they were only functioning on computerized intelligence. Think about it. The human brain has over a billion neurons, and our level of intelligence runs on only about 20 watts of power. Thats more than enough to play a marathon session of Pong.

Biological computing is the new frontier of computational power efficiency, the website says.

By the way, this wasnt the first time Pong got scientific star power. A.I. company DeepMind used it, along with other early Atari games that might be collecting dust in your basement somewhere, to demo how algorithms modeled after human neuron functions could perform. DeepMinds software scored high enough to convince Google into buying it. Now Google is using that tech to control the monster air conditioning units in its data centers, where it gets unbearably hot from servers devouring enough energy to keep entire cities running.

Cortical Labs is currently using mouse neurons on its quest to get hybrid chips to play Pong, but it probably wont be long before they use mutant human neurons. Gnarly.

(via Business Insider/Cortical Labs)

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Cyborg computer chips will get their brain from human neurons - SYFY WIRE

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Adrenoleukodystrophy is also known as Adrenomyeloneuropathy or Schilder-Addison Complex, it is a hereditary condition that damages the myelin sheath (membrane surrounding nerve cells in your brain) and disrupts the breakdown process of long-chain fatty acids (VLCFA). Adrenoleukodystrophy is passed down from parents to their children in a form of X-linked genetic trait. The genetic trait causes deposition of very-long chain fatty acids in the body tissues due to impaired beta oxidation. Myelin sheath in central nervous system, the adrenal cortex and Ledydig cells in the testes are the most severely affected tissues. Adrenoleukodystrophy give rise to three major disease categories such as childhood cerebral form (observed between 4 to 8 years of age), adrenomyelopathy and impaired adrenal gland function (also known as Addison disease).

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The major symptoms observed in a childhood cerebral form adrenoleukodystrophy patient are muscle spasms, crossed eyes (strabismus), hearing loss, seizures and other disorders related with the nervous system. In adrenomyelopathy the patients are observed with difficulty in controlling urination, muscle weakness or leg stiffness, difficulties in thinking speed and lack of visual memory. In Addison disease or adrenal gland failure the major symptoms observed are coma, decreased apetite, skin pigmentation, loss of weight, muscle weakness and vomiting. According to Centers for Disease Control and Prevention (CDC), approximately 1 in 20,000 people suffer from X-linked adrenoleukodystrophy. The Office of Rare Diseases (ORD) of the National Institutes of Health (NIH) has listed Adrenoleukodystrophy as a rare disease. In addition to this, CDC also reported that adrenoleukodystrophy, is a subtype of adrenoleukodystrophy, affects less than 200,000 people in the U.S. population annually.

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The adrenoleukodystrophy is diagnosed primarily with plasma very long chain fatty acid (VLCFA) examination by application of gas chromatography and/or mass spectrometery. The other diagnostics methods include chromosome studies that are carried out to understand the mutation in ABCD 1 gene and magnetic resonance imaging (MRI) scan of head. Adrenoleukodystrophy is treated with dietary therapy, transplant, adrenal insufficiency and gene therapy.

The dietary therapy consists of prohibiting the patient for the intake of very-long chain fatty acids (VLCFA) and this is a supportive therapy to normalize the disease conditions of the patient. The transplants are performed with allogeneic hematopoietic stem cells that assist in the demyelination process where myelin sheath is restored and its deterioration is inhibited. In gene therapy appropriate vectors are selected and modified according to the normal ABCD 1 and later these are transplanted into patients bone marrow or stem cell transplant. Adrenal insufficiency is the treatment still under research and trials as this process is ineffective and needs assistance form hormonal replacement therapy. In some cases genetic counseling is recommended for prospective parents with a family history of X-linked adrenoleukodystrophy.

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The product pipeline of adrenoleukodystrophy undergoing phase III trials is as follows:

North America was observed to be the leading geography followed by Europe due to high prevalence rate, increasing social awareness and key players based in the same geography. Asia-Pacific and Rest of the World lack due to unavailability and inaccessibility of the diagnostic techniques, counseling bodies and modern treatments.

The key players involved in the adrenoleukodystrophy therapeutics market are ,

Adrenoleukodystrophy is a rare disease hence the companies involved in therapeutics market of disease are few in number.

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Adrenoleukodystrophy Market Structure and Its Segmentation for the Period 2017 2025 - Curious Desk

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Scientists at Lund University in Sweden showed long ago they could reprogram human cells into nerve cells and implant them into the brains of rats after a stroke. But would the cells form the vital connections needed to restore mobility and sensations like touch?

Now, they have early evidence that the answer to that question isyes. The Lund team turned skin cells into nerve cells, transplanted them into the brains of the rodent stroke models and observed them for six months. The new cells repaired the damage caused by strokes in the animals, the researchers reported in the journal PNAS.

The Lund University team transplanted the reprogrammed skin cells into the rats cerebral cortices, the region of the brain thats most commonly damaged by stroke. Then they used electron microscopy and other technologies to track the cells. That allowed them to see that the cells were making the connections needed to repair damaged nerve circuits.

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We have been able to see that the fibers from the transplanted cells have grown to the other side of the brain, the side where we did not transplant any cells, and created connections, said co-author Zaal Kokaia, professor of neurology at Lund, in a statement.

RELATED: Restoring neurons to preserve memory after heart attack or stroke

Cell therapy has been proposed for treating stroke damage in the past, but efforts to make it a reality have hit some roadblocks. A stem cell therapy being developed by British biotech ReNeuron failed to hit its primary trial endpoint of improving arm and leg movements. ReNeuron has since turned in better results from a trial of its cell therapy for improving vision in patients with retinitis pigmentosa.

Meanwhile, academic researchers are testing a variety of other therapies aimed at repairing stroke damage. Last year, for example, Stanford researchers showed that blocking a particular microRNA prompted star-shaped brain cells called astrocytes to become neurons, which helped restore memory in rats.

The Lund team is now planning additional animal trials to study how their transplanted cells affect memory and other intellectual functions, they said. They will also watch the rats closely to make sure they arent experiencing side effects, and theyll study the impact of the transplants on regions of the brain.

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Cell therapy restores mobility and sensations in rodent models of stroke - FierceBiotech

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When Jeff Bezos, the Amazon kingpin, debuted his new muscular physique at the Sun Valley Conference in 2017, he almost broke the internet. His Vin Dieselesque guns launched countless memes about how the dweebs dweeb had transformed himself into a jacked-up specimen worthy of an action franchise.

In interviews Bezos credits his diet (which includes roast iguana and octopus for breakfast), his unwavering commitment to working out, and eight hours of sleep. But not everyone is buying it.

Clean livingthats the catchphrase, isnt it? quips Patricia Wexler, the ne plus ultra of Manhattan dermatologists. Very few admit to doing any procedures.

Not a chance its just diet and exercise, says Roberta Del Campo, a dermatologist based in Miami, the countrys plastic surgery capital. Behind the scenes these people are getting all sorts of injectables and body sculpting treatments, such as Emsculpt and Trusculpt Flex, which have surged in popularity, especially among men, in the last couple of years.

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Other experts suspect that captains of industry such as Bezos, who is 56, are going to even greater lengths to project vigor for both boards and broads. The tech titans are all looking much better than they used to, says Jessie Cheung, a Chicago-based cosmetic dermatologist whose holistic approach often involves testosterone and growth hormone substitutes, especially for men of a certain age who are lacking in muscle and look frail.

Access to bio-hacking tools such as stem cells and hormones is allowing men to look, perform, and think better. Its worth noting that Bezos, along with fellow billionaire Peter Thiel, invested in Unity Biotechnology, a company researching drugs and treatments to keep aging at bay. Im pretty sure hes gotten a taste of some good stuff, Cheung says.

Welcome to the new male vanity, in which even Silicon Valley bigwigs considerably younger than Bezos are resorting to newfangled procedures to avoid aging out of the workforce. The stakes have never been higher. American men underwent 1.1 million noninvasive cosmetic procedures in 2018a 72 percent increase since 2000, a trend that shows no signs of abating. In its forecast for 2020, the American Society for Aesthetic Plastic Surgery predicts the continued rise of the Daddy-Do-Over, the male equivalent of the Mommy Makeover, as men look to boost their confidence and improve their physical appearance.

Its a lesson in maintenance the men in the presidential race would do well to learn. In the not so distant past politicians could dismiss reporters questions about whether theyd had a face-lift, as Arnold Schwarzenegger did during his 2003 run for governor of California, when he joked that they must be confusing him with Cher. Now pols and pundits of every party are being grilled as mercilessly about their appearance as about their Medicare plans.

"Unfortunately for Biden, you can see the work thats been done," says one NYC dermatologist.

Joe Bidens forehead and Donald Trumps hair flap and skin color are dissected with the rigor of Kremlinologists (some of them actually are Kremlinologists, in Trumps case). And with good reason: If Hillary Clintons wrinkles, Elizabeth Warrens glasses, and Amy Klobuchars eyebrows are fair game, why not the nipped and tucked peacocks strutting around on Capitol Hill?

Denials about the scars on the side of Bidens face are, according to the experts, malarkey. Unfortunately for Biden, who has obviously had hair transplants and Botox, among other things, you can see the work thats been done, says Wexler. Nobody should be talking about work. When you have work done, the last thing you want is for people to notice it.

The queen of Fraxels laser focus on male primping is not partisan. Mr. Trump has definitely had workand not great work, at that, she adds. Give him his crumb, though: He wasnt bad looking when he was younger and in better shape.

Trumps penchant for cosmetic adjustments has been an open if much denied secret since at least 1991, when Ivana Trump disclosed his scalp reduction surgery and chin and waist liposuction in their divorce papers. In February the world was served a fresh reminder, when the president was photographed, in an image that quickly went viral, stepping out of Marine One with a windswept rug and a fake tan for the history books.

At tony dermatologist practices from coast to coast, man-tans like Trumps and obvious old-school work like the kind favored by Vladimir Putin is frowned uponif anyone can move any facial muscles at all. Instead, next-gen lasers such as NeoSkin by Aerolase, IBeam, and Nd:YAG are used to eliminate redness and discoloration.

Instead of surgical face-lifts, which, to be fair, remain popular in certain parts of the country (I definitely see them more on the West Coast, Wexler says, where its been around longer and is more accepted), men of means are turning to noninvasive procedures, most notably Ultherapy, a relatively painless FDA-cleared ultrasound treatment that requires no downtime.

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For the ultimate injection of masculine vigor, though, Cheung works with membersand not necessarily of Congress. We make penises bigger and better, she says. Self-confidence for men is tied up with their penises and how well they work. We give them their swagger back.

Men looking for an extra glide in their stride are considering the augmented Priapus Shot, or P-shot, Cheung says, a treatment thats the male equivalent of the O-shot. She is also increasingly recommending a machine called Emsella, better known as the Orgasm Throne, which generates approximately 11,000 Kegel contractions in 30 minutes (it was originally developed for female incontinence). It really gives you an invigorating kick in the pants, Cheung says.

If the recent past is anything to go by, theres no guarantee that the candidates who end up squaring off in November will provide anything resembling accurate medical recordswhich is a shame, as they would make interesting reading. Like Bezos and less heralded moguls across the country, they are unlikely to reveal any touch-ups to anyone but their best pals.

Men will come in and ask for something their friend has had done, Wexler says. But you wont hear anyone on Jimmy Fallon saying, Im so tired: I was at the dermatologist all day.

This story appears in the May 2020 issue of Town & Country.

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Jeff Bezos and the New Face of Male Vanity - TownandCountrymag.com

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Tyto Cares kit includes a connected otoscope among other things

Numerous startups offering telehealth or remote monitoring solutions closed funding rounds this week, despite slowing activity due to the Covid-19 pandemic. One of them is Tyto Care, a startup with a platform for at-home medical exams. It actually includes a kit with several tools that can allow physicians to remotely listen to a patients heart, measure their temperature, and image their throat and ears. Several hospitals in Israel, including Sheba Medical Center, deployed its technology to care for patients remotely.

On the biotech side, there were some notable rounds, too, including $70 million for Aspen Neuroscience, which is developing a new treatment for Parkinsons disease. The company was founded by Scripps Research Professor Emeritus Jeanne Loring, who developed a way to turn pluripotent skin cells derived from skin cells or other adult cells into neurons that produce dopamine.

Read more about the companies that recently raised funding:

Tyto Care

Funding amount: $50 million

Headquarters: New York, Israel

Tyto Care, a company that lets people conduct at-home medical exams, already saw rising demand before the Covid-19 pandemic. The company said it saw threefold growth in sales last year and has continued to see its users increase during the pandemic. Its at-home telehealth kit includes a handheld device with attachments that allow physicians to remotely listen to the heart and lungs, measure temperature, and look at the throat and ears during an exam.

The company closed an oversubscribed $50 million round, co-led by Insight Partners, Olive Tree Ventures and Qualcomm Ventures. Tyto Care plans to use the additional funds to further expand its footprint in the U.S., Europe and Asia, and add new features to its platform, such as home diagnostics.

Aspen Neuroscience

Funding amount: $70 million

Headquarters: San Diego, California

Aspen Neuroscience is developing a treatment for Parkinsons disease using a patients own cells. The company uses induced pluripotent stem cells to make dopamine-producing neurons, which are affected by the disease.

The company closed a $70 million series A round, led by New York-based healthcare investor OrbiMed, with participation from ARCH Venture Partners, Frazier Healthcare Partners, Domain Associates, Section 32 and Sam Altman.

We are impressed by the progress Aspen has made to date against its goals to develop innovative therapies to treat Parkinson disease and encouraged by the broader investment communitys support of the company, OrbiMed Managing Partner Jonathan Silverstein said in a news release.

The company plans to use the capital to fund the development of its lead candidate, including completing studies needed to submit an investigational new drug application to the FDA, and recruiting for clinical trials.

Tango Therapeutics

Funding amount: $60 million

Headquarters: Cambridge, Massachusetts

Tango Therapeutics, a biotechnology company focusing on developing cancer therapies, closed a $60 million series B round. The company is working on developing treatments to counteract the loss of tumor suppressor genes, reverse cancer cells ability to evade the immune system, and identify new combinations that are more effective than single-agent therapies. The oversubscribed financing was led by Boxer Capital, with additional new investors in Cormorant Asset Management and Casdin Capital.

SonderMind

Funding amount: $27 million

Headquarters: Denver, Colorado

SonderMind, a startup that matches users with in-network therapists, raised $27 million in funding. The series B round was led by prominent VC General Catalyst and F-Prime Capital. Existing investors include the Kickstart Seed Fund, Di?ko Ventures and Jonathan Bush.

The company has a large network of behavioral providers in Colorado, and is expanding in Texas and Arizona. It plans to use the proceeds of the funding round to expand its partnership with payors, employers and health systems.

SilverCloud

Funding amount: $16 million

Headquarters: Boston, Massachusetts

SilverCloud has seen an uptick in users tapping into its mental health programs for depression, anxiety and other conditions. The company raised a $30 million series B round, led by MemorialCare Innovation Fund, the VC arm of MemorialCare Health System. Other participating investors included LRVHealth, OSF Ventures and UnityPoint Health Ventures.

So far, the company had drummed up partnerships with more than 300 companies. Notably, it was also one of the products selected for Express Scripts first digital health formulary. SilverCloud said it would use the additional funds to expand access to mental health support services for healthcare professionals, as well as their families and their patients.

CyberMDX

Funding: $20 million

Headquarters: New York

Healthcare security startup CyberMDX closed a $20 million funding round. Sham, a French risk management and insurance provider, led the funding round, with participation from Pitango Venture Capital and Oure Ventures.

CyberMDX monitors a providers network for threats to its IT systems, connected medical devices, and other IoT devices. The company said it will use the $20 million to expand its platform to new markets.

Photo credit: Tyto Care

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Funding roundup: At-home medical exams and a Parkinson's treatment - MedCity News

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We can summon our cars with our smart phones, have a drone bring our wildest wishes to our door, and were just an Alexa and Roomba partnership away from having our own The Jetsonsstyle domestic assistant at our beck and call. In the world of aesthetics, futuristic procedures we never knew we needed are here now, too. These are todays top tweaks that prove the future is actually now.

Future FatMoving fat from one part of the body to another is a procedure that has been around since the late 1800s, and because fat transfers have been a reliable source of volume for faces, butts and breasts, their popularity continues to rise. Now, you dont even need your own fat to get a volume boost. Renuva is an alternative way to do fat transfers without liposuction, says Vero Beach, FL plastic surgeon Alan Durkin, MD. It can fill in scars and dimples, and plump hollow cheeks and hands. Instead of creating collagen, it induces natural human fat. When injected, Renuva acts as a scaffold that allows the body to stimulate its own fat cells to grow and divide creating organic fat. So, where does this fat come from? Dr. Durkin says its donated human tissue that is screened extensively and processed for quality and safety. It arrives in dehydrated form and we rehydrate it with saline before injecting it.

Glow GettersThink of microdroplets of filler as the Tiny House Nation of injectable rejuvenation. Although microdroplets have not yet been approved by the FDA in the United States, Juvderm Volite was created for this specific application and is being used extensively and successfully in Europe, says Bloomfield Hills, MI dermatologist Linda C. Honet, MD. Restylane Skinboosters Vital and Vital Lite are also used with the microinjection technique in Canada and marketed with a special microinjection syringe that delivers tiny amounts0.01 milliliters of fillerin a serial injection fashion. The main benefit of this approach? A consistent, superficial glow. We have found that when the hyaluronic acidbased filler is deposited in one area, deeper into the dermis, we still see the plumping and hydration in all areas of the skin,adds Beverly Hills, CA dermatologist Ava Shamban, MD.

A few years ago, under-eye carboxytherapy injection videos were going viral, as the insertion of carbon dioxide under the skin causes skin to inflate like a balloon. That visual hasnt stopped doctors from utilizing carboxytherapy to boost skin rejuvenation. The intent of carboxy injections is to increase oxygen in the skin by increasing capillary blood flow to eliminate carbon dioxide, says San Antonio dermatologist Vivian Bucay, MD. Now, a CO2 Lift mask gives similar benefits without the intense skin expansion. The mask is made of two gels that we mix together and apply on the skin, she adds. Although there are no formal studies to show carboxytherapy speeds recovery compared to other topicals, Dr. Bucay uses it after laser treatments, Ultherapy, microneedling and chemical peels to reduce healing time.

Miracle GrowWhen we think of getting something lasered, we tend to think of the skin- resurfacing treatments that obliterate layers of dead skin to reveal baby-fresh skin. But some doctors, like New York dermatologist Doris Day, MD, are harnessing laser energy to help hair grow in places where it hasnt for years. I use the Fotona laserit employs photobiomodulation, a form of gentle deep heatto stimulate the stem cells of dormant hair follicles and encourage regrowth. The laser energy penetrates the tissue, where it interacts with chromophores and induces a complex set of reactions that increases circulation, reduces inflammation and helps restore normal cellular function. Currently, there are no clinical studies to prove the efficacy of this hair growth treatment, but there are controlled studies being planned. Dr. Day has seen results with some patients as part of a long-term plan that also includes Nutrafol, DuoZyme supplements and quercetin, as well as topical treatments and sometimes platelet-rich plasma therapy.

Body MovinBelly buttons get an automatic upgrade during a tummy tuck or Mommy Makeover, but stand-alone umbilicoplasty is trending as patients continue to find small areas of their bodies to tinker with and perfect. And, its not just about turning an outie into an innie. Most of the belly button surgeries performed by Raleigh, NC plastic surgeon Michael Law, MD are on those who have had a tummy tuck with another doctor and are left with visible scarring, or their belly button has an odd, or operated-on look.

For tummies in need of extra tightening, theres a nonsurgical option being explored that involves the same polydioxanone (PDO) threads used in thread lifts for the face. Abdominal thread lifts are essentially retention sutures, which are placed into the lower, mid or upper abdomen to lift tissue, explains Spokane, WA dermatologist Wm. Philip Werschler, MD. Ideal candidates are those who arent surgical candidates, those who dont want surgery, or those whose concerns are less than what a typical tummy tuck would correct. The in-office procedure takes about one hour and is performed under local anesthetic. There are no current studies to show the efficacy or benefits of thread lifts in this area, but Dr. Werschler says he continues to see good results.

To slenderize the legs, calf reduction is actually a thing. Excess fat on the calves may result in the appearance of cankles being a bit shorter can also make the calves appear thicker, says Los Angeles plastic surgeon Peter Lee, MD. We can perform liposuction in order to trim them down to the patients goal size. Excision techniques may also be needed for the removal of excess tissue. To make calves look smaller without surgery, New York dermatologist Tatiana Khrom, MD uses Botox Cosmetic to reshape: We target the back of the lower leg, the gastrocnemius muscles, to slim the calves and help patients fit into their favorite boots or feel more confident in their shorts, with results lasting up to six months.

Important IntelAll the doctors included in this story mentioned how important creative, off-label use is to the medical communityand strongly stressed seeing a board-certified doctor, practicing within scope, who has vast experience and knowledge on the treatments in question. Off-label use can be safe when done by an experienced doctor who specializes in that off-label treatment; that doctor may also produce research showing efficacy of the off-label use, has been trained on the off-label use, or performs it regularly. Of course, all cosmetic treatments can have a potential risk whether on-or off-label and this is why its important to see a properly board-certified doctor.

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Cosmetic Treatments The New New Wave: Trending Treatments You've Never Heard of Until Now Apr - NewBeauty Magazine

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Bizizz Market Research has recently published a research report, 3D Bioprinting Market By Component (3D Bioprinters (Magnetic 3d bioprinting, Laser-assisted bioprinting, Inkjet 3d bioprinting, Micro extrusion Bioprinters, and Other) Bioprinters Bio inks (Natural bio inks, Synthetic bio inks, and Hybrid bio inks)), Material (Hydrogels, Extracellular Matrices, Living Cells, and Other Biomaterials), Application (Research Applications (Drug Research, Regenerative Medicine, 3d Cell Culture) Clinical Applications (Skin, Bone & Cartilage, Blood Vessels, and Others), End User (Hospitals, Research Organizations and Academic Institutes Biopharmaceutical, and Companies), and Region-Global Industry Trends, Estimation & Forecast, 2019 2027. As per the report,Global 3D Bioprinting Marketwas valued at US$ 623 Mn in 2018 and it is anticipated to reach at market value of US$ 1.4 Bn by 2027, witnessing a CAGR of 18.6 % during the forecast period. Key drivers of the market are increasing prevalence of chronic disorders like kidney and heart failures, growing elderly populace, and the insufficient number of organ donors. However, dearth of skilled professionals may hinder the growth of the market during the forecast period.

3D bioprinting technology has witnessed accelerated adoption in the healthcare industry. Bioprinting has emerged as a promising technological know-how for the fabrication of synthetic tissues and organs, which can revolutionize the analysis and cure of more than a few scientific conditions. Bioprinting businesses around the world are constantly innovating in regenerative medicine, tissue engineering, drug therapies, and stem cell therapy, which is gaining attention from healthcare authorities and pharmaceutical agencies to envision a future with higher patient care, custom-made medical treatment, and an alternative to organ transplantation.

Over the previous few years, essential technological advancements in the 3D bioprinting space have taken place for numerous scientific applications, inclusive of skin tissue development, most cancers therapeutics, bone and cartilage development, and liver modeling. Advanced technologies grant players with a competitive area and thereby help in strengthening their function and share in the market. For instance, in 2018, Poietis (France) launched the 3D bioprinted pores and skin model, Poieskin. The total human pores and skin model is made by using the bioprinting of essential human collagen and fibroblast for the dermal layer and major human keratinocytes for the epidermal layer.

The 3D Bioprinting market is anticipated to register a CAGR of over 18.6% during the forecast period.

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By Material, the living cells segment held a prominent share in Global3D BioprintingMarket in 2018.

On the basis of material, the 3D bioprinting market is segmented into hydrogels, extracellular matrices, living cells, and other biomaterials. In 2018, the living cells segment accounted for the biggest market share particularly due to the developing R&D in the fields of regenerative medicine and stem cell research, and increasing public and personal investments to help research

By Application, Skin Printing Segment of Global 3D Bioprinting Market Is Anticipated To Witness the Fastest CAGR during the Forecast Period

The clinical applications market is similarly segmented into skin printing, bone & cartilage printing, blood vessel printing, and other scientific applications. Among these, the pores and skin printing purposes segment is estimated to develop at the best CAGR of 19.8% in the course of the forecast period. This can be attributed to the technological developments and new product launches in this utility segment, and the growing wide variety of aesthetic and reconstruction surgeries across the globe.

North America is anticipated to dominate the Global 3D Bioprinting Market during the Forecast Period

Growing target populace base is in all likelihood to be the crucial cause boosting the regions 3D bioprinting market growth. The existence of well-established corporations and subtle healthcare set-up in consort with high income tiers in the location are also anticipated through the market development. Moreover, huge research and improvement activities carried out inside the place are said to make contributions to market expansion. Additionally, the accessibility of 3D printed drugs that can be tailor-made in accordance with the age and body weight of a person is supporting to boost up the market evolution.

Global 3D Bioprinting market was highly consolidated with key players accounting for significant share in 2018. Prominent players operating in the Global 3D Bioprinting Market are: Solidscape, Inc. (acquired by Prodways Group), TeVido BioDevices, LLC, 3Dynamics Systems Ltd., Bio3D Technologies Pte. Ltd., Aspect Biosystems Ltd., Stratasys Ltd., Luxexcel Group B.V., Materialise N.V., Cyfuse Biomedical K.K., Voxeljet A.G., Envision TEC, and Organovo Holding, Inc., among others.

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Our expanding team of professionals & experts from a wide array of streams and vertical has critical problem solving skills, innovative approaches and research techniques to deliver best solution to our clients. We continuously pushing our capabilities to enhance our services and setting higher quality goals each day. BMR offers syndicated reports, custom reports and consulting services to our clients. We are capable of catering the market research demands of individuals and organizations of various industries across different geographies with utmost data accuracy in minimal turnaround time.

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Global 3D Bioprinting Market is anticipated to reach at market value of US$ 1.4 Bn by 2027 - Galus Australis

Skin Stem Cells Comments Off on Global 3D Bioprinting Market is anticipated to reach at market value of US$ 1.4 Bn by 2027 – Galus Australis | April 10th, 2020

If you notice flakes in your hair or it's simply looking drab, chances are there's something making its home on your head that you definitely don't want there. Depending on your own pH levels, it could be the oil from clogged follicles creating dandruff, but even if you consider your scalp on the normal-to-dry side, product buildup can still linger on the scalp long after you've showered with shampoo and conditioner.

If you'd like to say a final farewell to product buildup, dead skin cells, and excess sebum, using a purifying scalp scrub once a week can exfoliate away dirt and flakes and leave your hair feeling cleaner than you've ever imagined. Beyond scrubs, other treatments like serums and oils can also help fortify follicles so hair grows back in healthier and stronger, plus treat the protective cuticle layer that locks in moisture and keeps hair looking shiny, too.

Check out the best hair-care products at Sephora that tackle everything from itchiness to dullness ahead, and give your scalp the special treat it's not-so-secretly seeking.

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Don't Be Flaky: Try One of These Scalp Treatments From Sephora and Get Your Scalp Right - POPSUGAR

Skin Stem Cells Comments Off on Don’t Be Flaky: Try One of These Scalp Treatments From Sephora and Get Your Scalp Right – POPSUGAR | April 8th, 2020

Theres a great deal of innovation embedded in todays cutting-edge computer chips, but not much of it is as out-of-the-box as the thinking thats driving Australian startup Cortical Labs. The company, like so many startups with artificial intelligence in mind, is building computer chips that borrow their neural network inspiration from the biological brain. The difference? Cortical is using actual biological neurons, taken from mice and humans, to make their chips.

Were building the first hybrid computer chip which entails implanting biological neurons on silicon chips, Hon Weng Chong, CEO and co-founder of Cortical Labs, told Digital Trends.

This is done by first extracting neurons in two different ways, either from a mouse embryo or by transforming human skin cells back into stem cells and inducing those to grow into human neurons.

We then grow those neurons in our laboratory on high density CMOS-based multi-electrode devices that contain 22,000 electrodes on tiny surfaces no larger than 7mm squared, Chong continued. These neurons form neural networks which then start to spontaneously fire electrical signals, after a two-week incubation period, that is picked up by our multi-electrode device. The multi-electrode device is also able to provide electrical stimulation.

The researchers arent the first to develop neural networks based on real neurons. Recently, scientists in the U.K., Switzerland, Germany, and Italy fired up a working neural network that allowed biological and silicon-based artificial brain cells to communicate with one another over an internet connection.A California startup called Koniku, meanwhile, is building silicon chips, created using mouse neurons, which are able to sense certain chemicals.

For now, research like Cortical Labs is still in a relatively early proof-of-concept stage. According to a recent article in Fortune, Cortical Labs current approach has less processing power than a dragonfly brain. That means that, for now, its pursuing humbler ambitions than its eventual goal.

While were still in the process of building the hybrid computer chip, right now were focused on shaping our neurons behavior to play a game of [Ataris] Pong, Chong said. Thats our next big milestone, which will provide a proof-of-concept similar to DeepMinds demonstration [in 2013] of its A.I. playing Breakout.

Commercialization is still a number of years away, Chong continued. But hes convinced it could be a game-changer. When we eventually take our final product to market we believe it will have a wide array of applications across robotics, cloud computing, and computer brain interfaces, he said. This does not include industries that we might not have thought about yet because of the novelty of such a computation paradigm.

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Meet the sci-fi startup building computer chips with real biological neurons - Digital Trends

Skin Stem Cells Comments Off on Meet the sci-fi startup building computer chips with real biological neurons – Digital Trends | April 8th, 2020

The coronavirus crisis is affecting every aspect of our lives, including the condition of our skin. Have you noticed that your skin is particularly spotty, irritated and angry lately? That's another thing you can blame on COVID-19.

Express.co.ukspoke to Dr. Luca Russo, Dermatologist at Urban Retreat, to find out why.Dr. Russo says there are several reasons for your unexpected breakouts.He said: "There might be several reasons for noticing a tendency to break out during this national emergency."It's probably to do with what's going on inside, and what you're putting in your body, says Dr. Russo.

READ MORE- Coronavirus symptoms: Man reveals skin-related warning sign

Are you up all night worrying about the virus?Dr. Russo says: "The most likely cause of your breakout is stress."During such uncertain and stressful times, our system copes with increased production of Cortisol."Cortisol is an androgen hormone that is released when we are facing unusual challenges and prepare us to "fight'."However, it will also increase the sugar level in the bloodstream and production of sebum that might be a cause of the breakout."

In order to prevent breakouts that stem from high levels of stress, you'll need to calm yourself down.Dr Russo recommends doing activities that allow you to relax and unwind, such as yoga.He also suggests exercising regularly, so it's time to start making use of that daily government-approved walk, cycle, or run.

If you hate exercising, don't worry, the antidote to high cortisol levels doesn't have to be physical.Laughing, a solid night of sleep, or practising your favourite hobby are all effective options.

Having a soak in the bath and doing a face-mask may help you feel more in control of your skin.

This relief may cause a decrease in oil production and pimples.

DON'T MISS...How to help your brain through the coronavirus crisis stress [EXPLAINER]Coronavirus: How to look after your mental health during lockdown [EXPLAINER]Lockdown exercise: The eight exercises you can do at home [INFORMER]

Can you honestly say you have been eating well throughout the lockdown?Most people have stocked up on sugary treats and salty snacks in order to cheer themselves up in the face of COVID-19.And what about the good-old "support local businesses" excuse you use every time you order a greasy takeaway?Dr Russo says: "During isolation food becomes one of the few focal points of the day with more consumption of comfort food."Just like any other organ in your body, a poor diet affects your skin negatively.The body breaks down our food into tiny particles of proteins, fats, and carbs, and circulates it to the organs that need them.These nutrients make their way to your skin too, impacting its condition.It makes sense that inflammatory foods, such as sweets, some dairy, processed meat, and refined carbohydrates, will cause a flare-up in your complexion.

Dr. Russo says: "To improve your skin, you must eat well."Eat foods that are packed with vitamins and proteins and snack on fruit and veg."Drinking lots of water will replace the moisture that is lost through sweat and other processes, keeping your skin hydrated.If you fill up on foods rich in healthy oils and omega-3 fatty acids, you will improve the collagen production in your skin.This makes your skin smoother, suppler, and will help you in the longterm by preventing premature ageing.These oils and fats are found in fish, nuts, olive oil, and many more commonly found items.

During the lockdown, we're stuck inside all day and often don't get a chance to let our skin feel the sun.Dr. Russo says: "At the moment, skin isn't being exposed to natural light much at all."When your skin is exposed to natural light, the production of Vitamin D is increased."Endorphins are also produced, and this boosts your immune system and well-being."Make sure you get some fresh air every day, in order to reap these benefits of the sun.The sun is a great natural resource to improve your skin, but make sure you protect yourself with sun protection before you go out.You should wear an SPF of at least 30 on your face whenever you leave the house or are in front of a window for a prolonged amount of time.

Most people are shunning makeup in favour of the natural look since no one other than our household is going to see our faces.This means you may be tempted to skip your cleansing routine and go straight to bed once the day is over.

If you normally get facials and now can't, this may also be why you are breaking out or seeing changes.Dr. Russo explains: "You have probably been unable to receive professional treatments over this time, and this will contribute towards your breakouts."Dr. Russo recommends continuing with your normal skincare routine.He says: "Carry on as normal, but add an exfoliating cleanser to your routine."Exfoliating cleansers make your skincare routine shorter, by combining exfoliating and cleansing in one step.They remove dead skin cells and any build-up of dirt and oil in one go.There are hundreds of physical exfoliating cleansers on the market, as well as chemical exfoliating cleansers, so take your pick!

While surgical masks are thought to protect us against coronavirus, they're not great for our skin, said Dr. Russo.Wearing a mask over your face for many hours is damaging to your skin, especially when it's hot outside.The mask offers the perfect spot for bacteria and germs to harbour.Try double cleansing on the lower half of your face if you've worn a surgical mask for a prolonged period of time.

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Lockdown skin: Why is my skin worse even though I'm not wearing any makeup? - Express

Skin Stem Cells Comments Off on Lockdown skin: Why is my skin worse even though I’m not wearing any makeup? – Express | April 8th, 2020

Theres a great deal of innovation embedded in todays cutting-edge computer chips, but not much of it is as out-of-the-box as the thinking thats driving Australian startup Cortical Labs. The company, like so many startups with artificial intelligence in mind, is building computer chips that borrow their neural network inspiration from the biological brain. The difference? Cortical is using actual biological neurons, taken from mice and humans, to make their chips.

Were building the first hybrid computer chip which entails implanting biological neurons on silicon chips, Hon Weng Chong, CEO and co-founder of Cortical Labs, told Digital Trends.

This is done by first extracting neurons in two different ways, either from a mouse embryo or by transforming human skin cells back into stem cells and inducing those to grow into human neurons.

We then grow those neurons in our laboratory on high density CMOS-based multi-electrode devices that contain 22,000 electrodes on tiny surfaces no larger than 7mm squared, Chong continued. These neurons form neural networks which then start to spontaneously fire electrical signals, after a two-week incubation period, that is picked up by our multi-electrode device. The multi-electrode device is also able to provide electrical stimulation.

The researchers arent the first to develop neural networks based on real neurons. Recently, scientists in the U.K., Switzerland, Germany, and Italy fired up a working neural network that allowed biological and silicon-based artificial brain cells to communicate with one another over an internet connection.A California startup called Koniku, meanwhile, is building silicon chips, created using mouse neurons, which are able to sense certain chemicals.

For now, research like Cortical Labs is still in a relatively early proof-of-concept stage. According to a recent article in Fortune, Cortical Labs current approach has less processing power than a dragonfly brain. That means that, for now, its pursuing humbler ambitions than its eventual goal.

While were still in the process of building the hybrid computer chip, right now were focused on shaping our neurons behavior to play a game of [Ataris] Pong, Chong said. Thats our next big milestone, which will provide a proof-of-concept similar to DeepMinds demonstration [in 2013] of its A.I. playing Breakout.

Commercialization is still a number of years away, Chong continued. But hes convinced it could be a game-changer. When we eventually take our final product to market we believe it will have a wide array of applications across robotics, cloud computing, and computer brain interfaces, he said. This does not include industries that we might not have thought about yet because of the novelty of such a computation paradigm.

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Meet the sci-fi startup building computer chips with real biological neurons - Yahoo Tech

Skin Stem Cells Comments Off on Meet the sci-fi startup building computer chips with real biological neurons – Yahoo Tech | April 6th, 2020

'Let me tell you about the very rich,' wrote F Scott Fitzgerald. 'They are different from you and me.' Above all, in the lengths they will go to acquire, and preserve, perfect skin.

Sheikha Moza bint Nasser, the consort of the former Emir of Qatar, may well be the richest person I've ever met. She certainly has skin like no one else on the planet. She's 61 but looks about 40, with a face that seems to have no visible pores, perhaps because it's sculpted out of alabaster.

Admittedly, she is carefully made-up on a regular basis, so she would have been unlikely to want to attend a recent dinner party of Gwyneth Paltrow's in Beverly Hills, at which guests were banned from wearing any cosmetics at all. Kate Hudson and Demi Moore were among those who gamely took the challenge, the idea of which was to allow the assembled LA A-listers to show off their natural glow.

But they don't, of course, rely wholly on nature for their radiance. Moore's evening beauty routine (pared back to the minimum because, she says, "I like to keep it simple") includes eight separate products, with a total cost of 743.50, from a cleansing elixir to a 355 replenishing facial oil and a rose-quartz facial massager in the shape of a butterfly.

No wonder that, far from being petrified at the thought of the make-up-free dinner, she felt 'full of joy', according to her Instagram posts. Her face wasn't coated in foundation, but it was insulated by a thick layer of cash.

With skincare that promises actually to reverse the visible signs of ageing, beauty brands feel entitled to charge impressive sums. La Prairie has one serum, its Platinum Night Elixir, that sells for over 1,000 for 20ml. It costs about 10 more per gram than solid gold. Imagine if your cat knocked that one off the dressing table.

On the other hand, the scientist who developed it says the peptides and amino acids contained in a single daily drop will leave your skin visibly younger-looking and fresher in two weeks. Users say it feels like wrapping your face in cashmere.

La Prairie Platinum Rare Cellular Night Elixir 20ml, 1,018, Harvey Nichols

I rely on Dr Phillip Levy, a Swiss dermatologist and wound-healing specialist based in Geneva, whose moisturisers and serums are proven to revitalise dermal stem cells to kick-start your skin's own production of collagen. Another doctor - German-born Michael Prager, who operates from a clinic in Wimpole Street - emphasises the rejuvenating effects of combating pollution with an antioxidant cream that fights off free radicals.

Neither of these medical-grade ranges comes cheap, but though Dr Prager's day oil contains pure gold, at 225 for 30ml (drmichaelprager.com), it's not actually as expensive as buying the precious metal itself.

If you're going down the Sheikha Moza route to moneyed perfection with a lavish use of make-up, Gucci Westman is a name to conjure with. This make-up artist, who has worked with Natalie Portman and Nicole Kidman, has her own range, Westman Atelier.

Lip suede in Les Rouges, 75, Westman Atelier (net-a-porter.com)

Yes, the colours are lush but, even better, the brand is 'clean' - beauty-speak for vegan, against animal-testing, paraben-free and so on. Plus, the products moisturise, plump up collagen and soothe as you apply them. Even the mascara conditions your lashes. So what if it costs 58?

Equally impressive is Shiseido's luxury line, Cl de Peau, which does a foundation that's 250 for 27ml, in 13 shades. Again, it's a beauty treatment with SPF and moisturiser as much as a make-up product, and it's what I'll put on if I want anyone to tell me I look glowing.

But, of course, more precious than any cream or blush stick is a little personal attention. Dr Costas Papageorgiou operates out of Harrods and has fairly expensive-looking skin himself. He makes use of a battery of lasers, Botox, fillers and ultrasound, but the key to his success is the consultation that starts off the process.

The Foundation,250, Cl de Peau Beaut (harrods.com)

Seeing your own face in unforgiving 3D on a computer may be a shock, but it certainly helps pinpoint the areas you'd like him to focus on. He's very hot on correcting facial symmetry, which starts out pretty good in babies, but with time and use, the muscles on the face become less symmetrical as bits start to droop or wrinkle. Generally, the more lopsided you are, the more antique you look, and he can address that with filler, Botox and even thread lifts.

But I'm not one for the injectables. It's his Hybrid Energy Lift - a combination of ultrasound, infrared, light and laser - that I really rate (from 6,000 for 120 minutes, facialplasticslondon.com). It, too, stimulates collagen production, but it also gets rid of visible veins and redness, and even reduces big pores. I have had to change the tone of my foundation for a paler one since he did for my (mild) rosacea.

Radical3 Reboot Pro Peel, 89, Dr Levy (editorslist.co.uk)

The key, says Dr Papageorgiou, is to delay and reverse the "ageing cascade". This slow car crash of fine lines around the eyes, sun damage and heavy jowls is all thanks, he says, to "fat atrophy and bone resorption".

But subtlety is all - "A great result is one that shows no signs of intervention"- and nothing, he warns, can really be achieved unless you have a healthy diet, exercise and take vitamins.

Debbie Thomas, at her D.Thomas clinic in London, has a similarly personalised approach. You don't book in for a single treatment, you book for an hour of her expert time, and she'll use a cocktail of lasers, micro-needling and products depending on what you need (475 for a DNA Laser Complete 2 session, dthomas.com).

"I'm afraid,"she says, "traditional facials are not going to transform your skin for more than a few days. You need to upgrade to more advanced treatments if you want long-term results. And those will be more costly."And who can say it's not worth the money?

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The rise of 'rich woman face': how to halt the ageing process (for a certain price) - Telegraph.co.uk

Skin Stem Cells Comments Off on The rise of ‘rich woman face’: how to halt the ageing process (for a certain price) – Telegraph.co.uk | April 6th, 2020