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George Cotsarelis - One of the best experts on this subject based on the ideXlab platform.
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The Hair Follicle as a target for gene therapy
Annales de dermatologie et de venereologie, 2020Co-Authors: George CotsarelisAbstract:The Hair Follicle possesses progenitor cells required for continuous Hair Follicle cycling and for epidermal keratinocytes, melanocytes and Langerhans cells. These different cell types can be the target of topical gene delivery in the skin of the mouse. Using a combination of liposomes and DNA, we demonstrate the feasibility of targeting Hair Follicle cells in human scalp xenografts. We consider liposome composition and stage of the Hair cycle as important parameters influencing transfection of human Hair Follicles. Transfection is possible only during the early anagen phase. Factors and obstacles for the use of gene therapy in treating alopecia and skin diseases are discussed. A theoretical framework for future treatment of cutaneous and systemic disorders using gene therapy is presented.
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bald scalp in men with androgenetic alopecia retains Hair Follicle stem cells but lacks cd200 rich and cd34 positive Hair Follicle progenitor cells
Journal of Clinical Investigation, 2011Co-Authors: Luis A Garza, Chaochun Yang, Tailun Zhao, Hanz Blatt, Helen He, David C Stanton, Lee Carrasco, Jeffrey H Spiegel, John W Tobias, George CotsarelisAbstract:Androgenetic alopecia (AGA), also known as common baldness, is characterized by a marked decrease in Hair Follicle size, which could be related to the loss of Hair Follicle stem or progenitor cells. To test this hypothesis, we analyzed bald and non-bald scalp from AGA individuals for the presence of Hair Follicle stem and progenitor cells. Cells expressing cytokeratin15 (KRT15), CD200, CD34, and integrin, α6 (ITGA6) were quantitated via flow cytometry. High levels of KRT15 expression correlated with stem cell properties of small cell size and quiescence. These KRT15hi stem cells were maintained in bald scalp samples. However, CD200hiITGA6hi and CD34hi cell populations — which both possessed a progenitor phenotype, in that they localized closely to the stem cell–rich bulge area but were larger and more proliferative than the KRT15hi stem cells — were markedly diminished. In functional assays, analogous CD200hiItga6hi cells from murine Hair Follicles were multipotent and generated new Hair Follicles in skin reconstitution assays. These findings support the notion that a defect in conversion of Hair Follicle stem cells to progenitor cells plays a role in the pathogenesis of AGA.
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review of Hair Follicle dermal cells
Journal of Dermatological Science, 2010Co-Authors: Chaochun Yang, George CotsarelisAbstract:Hair Follicle stem cells in the epithelial bulge are responsible for the continual regeneration of the Hair Follicle during cycling. The bulge cells reside in a niche composed of dermal cells. The dermal compartment of the Hair Follicle consists of the dermal papilla and dermal sheath. Interactions between Hair Follicle epithelial and dermal cells are necessary for Hair Follicle morphogenesis during development and in Hair reconstitution assays. Dermal papilla and dermal sheath cells express specific markers and possess distinctive morphology and behavior in culture. These cells can induce Hair Follicle differentiation in epithelial cells and are required in Hair reconstitution assays either in the form of intact tissue, dissociated freshly prepared cells or cultured cells. This review will focus on Hair Follicle dermal cells since most therapeutic efforts to date have concentrated on this aspect of the Hair Follicle, with the idea that enriching Hair-inductive dermal cell populations and expanding their number by culture while maintaining their properties, will establish an efficient Hair reconstitution assay that could eventually have therapeutic implications.
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wnt dependent de novo Hair Follicle regeneration in adult mouse skin after wounding
Nature, 2007Co-Authors: Zaixin Yang, Sarah E Millar, Thomas Andl, George CotsarelisAbstract:The mammalian Hair Follicle is thought to form anew only during development, and loss of an adult Follicle is generally considered permanent. Fifty years ago in Nature, Billingham and Russel reported 'Hair neogenesis' in rabbit skin, but this was later discounted. Now it is back, with the discovery that Hair Follicle regeneration is triggered by wounding the skin of adult mice. This suggests that mammalian skin responds to wounding with greater plasticity and regenerative capacity than was previously believed, and has implications for those studying wound healing, tissue regeneration and stem cell function. The mammalian Hair Follicle was thought to form only during development, so loss of an adult Follicle was considered permanent. Here Cotsarelis and colleagues solve a fifty-year-old debate, and show that wounding the skin of adult mice triggers de novo Hair Follicle regeneration. The mammalian Hair Follicle is a complex ‘mini-organ’ thought to form only during development1; loss of an adult Follicle is considered permanent. However, the possibility that Hair Follicles develop de novo following wounding was raised in studies on rabbits2,3, mice4 and even humans fifty years ago5. Subsequently, these observations were generally discounted because definitive evidence for follicular neogenesis was not presented6. Here we show that, after wounding, Hair Follicles form de novo in genetically normal adult mice. The regenerated Hair Follicles establish a stem cell population, express known molecular markers of Follicle differentiation, produce a Hair shaft and progress through all stages of the Hair Follicle cycle. Lineage analysis demonstrated that the nascent Follicles arise from epithelial cells outside of the Hair Follicle stem cell niche, suggesting that epidermal cells in the wound assume a Hair Follicle stem cell phenotype. Inhibition of Wnt signalling after re-epithelialization completely abrogates this wounding-induced folliculogenesis, whereas overexpression of Wnt ligand in the epidermis increases the number of regenerated Hair Follicles. These remarkable regenerative capabilities of the adult support the notion that wounding induces an embryonic phenotype in skin, and that this provides a window for manipulation of Hair Follicle neogenesis by Wnt proteins. These findings suggest treatments for wounds, Hair loss and other degenerative skin disorders.
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capturing and profiling adult Hair Follicle stem cells
Nature Biotechnology, 2004Co-Authors: Rebecca J Morris, Lee Marles, Zaixin Yang, Carol S Trempus, Shulan Li, Janet A Sawicki, George CotsarelisAbstract:The Hair Follicle bulge possesses putative epithelial stem cells. Characterization of these cells has been hampered by the inability to target bulge cells genetically. Here, we use a Keratin1-15 (Krt1-15, also known as K15) promoter to target mouse bulge cells with an inducible Cre recombinase construct or with the gene encoding enhanced green fluorescent protein (EGFP), which allow for lineage analysis and for isolation of the cells. We show that bulge cells in adult mice generate all epithelial cell types within the intact Follicle and Hair during normal Hair Follicle cycling. After isolation, adult Krt1-15-EGFP-positive cells reconstituted all components of the cutaneous epithelium and had a higher proliferative potential than Krt1-15-EGFP-negative cells. Genetic profiling of Hair Follicle stem cells revealed several known and unknown receptors and signaling pathways important for maintaining the stem cell phenotype. Ultimately, these findings provide potential targets for the treatment of Hair loss and other disorders of skin and Hair.
Robert M Hoffman - One of the best experts on this subject based on the ideXlab platform.
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Hair Follicle Pluripotent Stem (hfPS) Cells
Human Adult Stem Cells, 2020Co-Authors: Robert M HoffmanAbstract:Our laboratory has discovered that nestin, a protein marker for neural stem cells is also expressed in Hair Follicle stem cells and their immediate, differentiated progeny. The fluorescent protein, GFP, whose expression is driven by the nestin regulatory element in transgenic mice (ND-GFP mice), served to mark Hair Follicle stem cells and enabled us to make this observation. The ND-GFP Hair-Follicle stem cells are positive for the stem cell marker CD34 but negative for keratinocyte marker keratin 15, suggesting their relatively undifferentiated state. We have shown that these Hair Follicle stem cells can differentiate into neurons, glia, keratinocytes, smooth muscle cells and melanocytes in vitro. In vivo studies show the Hair Follicle stem cells can differentiate into blood vessels and neural tissue after transplantation to the subcutis of nude mice. Hair Follicle stem cells implanted into the gap region of severed sciatic or tibial nerves greatly enhance the rate of nerve regeneration and the restoration of nerve function. When transplanted to severed nerves in mice, the Follicle cells transdifferentiate largely into Schwann cells, which are known to support neuron regrowth. The transplanted mice regain the ability to walk normally. We have also shown that Hair Follicle stem cells can affect the functional joining of the severed spinal cord. When the Hair Follicle stem cells are injected into the severed spinal cord, they differentiate into Schwann cells enabling the cord to rejoin and the mouse to regain function of its rear legs. Thus, Hair Follicle pluripotent stem (hfPS) cells can provide an effective, accessible, autologous source of stem cells for treatment of peripheral nerve injury and appear to be a paradigm for adult stem cells.
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Protocols for Cryopreservation of Intact Hair Follicle That Maintain Pluripotency of Nestin-Expressing Hair-Follicle-Associated Pluripotent (HAP) Stem Cells.
Methods of Molecular Biology, 2016Co-Authors: Satoshi Kajiura, Lingna Li, Robert M Hoffman, Yuko Hamada, Nobuko Arakawa, Katsumasa Kawahara, Kensei Katsuoka, Yasuyuki AmohAbstract:: Hair Follicles contain nestin-expressing pluripotent stem cells, the origin of which is above the bulge area, below the sebaceous gland. We have termed these cells Hair-Follicle-associated pluripotent (HAP) stem cells. Cryopreservation methods of the Hair Follicle that maintain the pluripotency of HAP stem cells are described in this chapter. Intact Hair Follicles from green fluorescent protein (GFP) transgenic mice were cryopreserved by slow-rate cooling in TC-Protector medium and storage in liquid nitrogen. After thawing, the upper part of the Hair Follicle was isolated and cultured in DMEM with fetal bovine serum (FBS). After 4 weeks culture, cells from the upper part of the Hair Follicles grew out. The growing cells were transferred to DMEM/F12 without FBS. After 1 week culture, the growing cells formed Hair spheres, each containing approximately 1 × 10(2) HAP stem cells. The Hair spheres contained cells which could differentiate to neurons, glial cells, and other cell types. The formation of Hair spheres by the thawed and cultured upper part of the Hair Follicle produced almost as many pluripotent Hair spheres as fresh Follicles. The Hair spheres derived from cryopreserved Hair Follicles were as pluripotent as Hair spheres from fresh Hair Follicles. These results suggest that the cryopreservation of the whole Hair Follicle is an effective way to store HAP stem cells for personalized regenerative medicine, enabling any individual to maintain a bank of pluripotent stem cells for future clinical use.
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Cryopreservation of the Hair Follicle Maintains Pluripotency of Nestin-Expressing Hair Follicle-Associated Pluripotent Stem Cells
Tissue Engineering Part C-methods, 2015Co-Authors: Satoshi Kajiura, Lingna Li, Robert M Hoffman, Yuko Hamada, Nobuko Arakawa, Katsumasa Kawahara, Kensei Katsuoka, Yasuyuki AmohAbstract:Hair Follicles contain nestin-expressing pluripotent stem cells, the origin of which is above the bulge area, below the sebaceous gland. We have termed these cells Hair Follicle-associated pluripotent (HAP) stem cells. In the present study, we established efficient cryopreservation methods of the Hair Follicle that maintained the pluripotency of HAP stem cells. We cryopreserved the whole Hair Follicle from green fluorescent protein transgenic mice by slow-rate cooling in TC-Protector medium and storage in liquid nitrogen. After thawing, the upper part of the Hair Follicle was isolated and cultured in Dulbecco's Modified Eagle's Medium (DMEM) with fetal bovine serum (FBS). After 4 weeks of culture, cells from the upper part of the Hair Follicle grew out. The growing cells were transferred to DMEM/F12 without FBS. After 1 week of culture, the growing cells formed Hair spheres, each containing ∼1×102 HAP stem cells. The Hair spheres contained cells that differentiated to neurons, glial cells, and other cell ...
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nestin expressing Hair Follicle accessible pluripotent stem cells for nerve and spinal cord repair
Cells Tissues Organs, 2015Co-Authors: Robert M HoffmanAbstract:Nestin-expressing stem cells of the Hair Follicle, discovered by our laboratory, have been shown to be able to form neurons and other nonFollicle cell types. We have shown that the nestin-expressing stem cells from the Hair Follicle can effect the repair of peripheral nerve and spinal cord injury. The Hair Follicle stem cells differentiate into neuronal and glial cells after transplantation to the injured peripheral nerve and spinal cord, and enhance injury repair and locomotor recovery. We have termed these cells Hair Follicle-accessible pluripotent (HAP) stem cells. When the excised Hair Follicle with its nerve stump was placed in Gelfoam® 3D histoculture, HAP stem cells grew and extended the Hair Follicle nerve which consisted of βIII-tubulin-positive fibers with F-actin expression at the tip. These findings indicate that βIII-tubulin-positive fibers elongating from the whisker Follicle sensory nerve stump were growing axons. The growing whisker sensory nerve was highly enriched in HAP stem cells, which appeared to play a major role in its elongation and interaction with other nerves in 3D Gelfoam® histoculture, including the sciatic nerve, the trigeminal nerve, and the trigeminal nerve ganglion. Our results suggest that a major function of the HAP stem cells in the Hair Follicle is for growth of the Follicle sensory nerve. HAP stem cells have critical advantages over embryonic stem cells and induced pluripotent stem cells in that they are highly accessible, require no genetic manipulation, are nontumorigenic, and do not present ethical issues for regenerative medicine.
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The pluripotency of Hair Follicle stem cells.
Cell Cycle, 2006Co-Authors: Robert M HoffmanAbstract:The Hair Follicle bulge area is an abundant, easily accessible source of actively growing, pluripotent adult stem cells. Nestin, a protein marker for neural stem cells, is also expressed in Follicle stem cells as well as their immediate differentiated progeny. The nestin-expressing Hair Follicle stem cells differentiated into neurons, glial cells, keratinocytes and smooth muscle cells in vitro. Hair-Follicle stem cells were implanted into the gap region of a severed sciatic nerve. The Hair Follicle stem cells greatly enhanced the rate of nerve regeneration and the restoration of nerve function. The Follicle cells transdifferentiated largely into Schwann cells which are known to support neuron regrowth. Function of the rejoined sciatic nerve was measured by contraction of the gastrocnemius muscle upon electrical stimulation. After severing the tibial nerve and subsequent transplantation of Hair-Follicle stem cells, the transplanted mice recovered the ability to walk normally. These results suggest that hai...
Ralf Paus - One of the best experts on this subject based on the ideXlab platform.
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the Hair Follicle as a dynamic miniorgan
Current Biology, 2009Co-Authors: Marlon R Schneider, Ralf Paus, Ruth SchmidtullrichAbstract:Hair is a primary characteristic of mammals, and exerts a wide range of functions including thermoregulation, physical protection, sensory activity, and social interactions. The Hair shaft consists of terminally differentiated keratinocytes that are produced by the Hair Follicle. Hair Follicle development takes place during fetal skin development and relies on tightly regulated ectodermal-mesodermal interactions. After birth, mature and actively growing Hair Follicles eventually become anchored in the subcutis, and periodically regenerate by spontaneously undergoing repetitive cycles of growth (anagen), apoptosis-driven regression (catagen), and relative quiescence (telogen). Our molecular understanding of Hair Follicle biology relies heavily on mouse mutants with abnormalities in Hair structure, growth, and/or pigmentation. These mice have allowed novel insights into important general molecular and cellular processes beyond skin and Hair biology, ranging from organ induction, morphogenesis and regeneration, to pigment and stem cell biology, cell proliferation, migration and apoptosis. In this review, we present basic concepts of Hair Follicle biology and summarize important recent advances in the field.
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Hair Follicle stem cells walking the maze
European Journal of Cell Biology, 2007Co-Authors: Stephan Tiede, Jennifer E Kloepper, Eniko Bodo, Sanjay Tiwari, Charli Kruse, Ralf PausAbstract:The discovery of epithelial stem cells (eSCs) in the bulge region of the outer root sheath of Hair Follicles in mice and man has encouraged research into utilizing the Hair Follicle as a therapeutic source of stem cells (SCs) for regenerative medicine, and has called attention to the Hair Follicle as a highly instructive model system for SC biology. Under physiological circumstances, bulge eSCs serve as cell pool for the cyclic regeneration of the anagen Hair bulb, while they can also regenerate the sebaceous gland and the epidermis after injury. More recently, melanocyte SCs, nestin+, mesenchymal and additional, as yet ill-defined “stem cell” populations, have also been identified in or immediately adjacent to the Hair Follicle epithelium, including in the specialized Hair Follicle mesenchyme (connective tissue sheath), which is crucial to wound healing. Thus the Hair Follicle and its adjacent tissue environment contain unipotent, multipotent, and possibly even pluripotent SC populations of different developmental origin. It provides an ideal model system for the study of central issues in SC biology such as plasticity and SC niches, and for the identification of reliable, specific SC markers, which distinguish them from their immediate progeny (e.g. transient amplifying cells). The current review attempts to provide some guidance in this growing maze of Hair Follicle-associated SCs and their progeny, critically reviews potential or claimed Hair Follicle SC markers, highlights related differences between murine and human Hair Follicles, and defines major unanswered questions in this rapidly advancing field.
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Hair Follicle pigmentation
Journal of Investigative Dermatology, 2005Co-Authors: Andrzej Slominski, Ralf Paus, Jacobo Wortsman, Przemyslaw M Plonka, Karin U Schallreuter, Desmond J. TobinAbstract:Hair shaft melanin components (eu- or/and pheomelanin) are a long-lived record of precise interactions in the Hair Follicle pigmentary unit, e.g., between follicular melanocytes, keratinocytes, and dermal papilla fibroblasts. Follicular melanogenesis (FM) involves sequentially the melanogenic activity of follicular melanocytes, the transfer of melanin granules into cortical and medulla keratinocytes, and the formation of pigmented Hair shafts. This activity is in turn regulated by an array of enzymes, structural and regulatory proteins, transporters, and receptors and their ligands, acting on the developmental stages, cellular, and Hair Follicle levels. FM is stringently coupled to the anagen stage of the Hair cycle, being switched-off in catagen to remain absent through telogen. At the organ level FM is precisely coupled to the life cycle of melanocytes with changes in their compartmental distribution and accelerated melanoblast/melanocyte differentiation with enhanced secretory activity. The melanocyte compartments in the upper Hair Follicle also provides a reservoir for the repigmentation of epidermis and, for the cyclic formation of new anagen Hair bulbs. Melanin synthesis and pigment transfer to bulb keratinocytes are dependent on the availability of melanin precursors, and regulation by signal transduction pathways intrinsic to skin and Hair Follicle, which are both receptor dependent and independent, act through auto-, para- or intracrine mechanisms and can be modified by hormonal signals. The important regulators are MC1 receptor its and adrenocorticotropic hormone, melanocyte stimulating hormone, agouti protein ligands (in rodents), c-Kit, and the endothelin receptors with their ligands. Melanin itself has a wide range of bioactivities that extend far beyond its determination of Hair color.
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the Hair Follicle and immune privilege
The journal of investigative dermatology. Symposium proceedings the Society for Investigative Dermatology Inc. [and] European Society for Dermatologic, 2003Co-Authors: Ralf Paus, Masahiro TakigawaAbstract:This essay reviews the available evidence that the proximal Hair Follicle epithelium generates and maintains an area of relative immune privilege during a defined segment of the Hair cycle (i.e., during anagen). This immune privilege is chiefly characterized by a very low level of expression of MHC class Ia antigens and by the local production of potent immunosuppressive agents, such as α-MSH and TGF-β1. We discuss the putative functions of immune privilige of the anagen Hair bulb, favoring the view that immune privilege serves mainly to sequester anagen- and/or melanogenesis-associated autoantigens from immune recognition by autoreactive CD8+ T cells. On this basis, we develop how the "immune privilege collapse model" of alopecia areata pathogenesis was conceived. In our discussion of the clinical implications of immune privilege, we outline the currently available evidence in support of this still hypothetical scenario to explain the initiation, progression, and termination of alopecia areata lesions. We review the most recent evidence from our laboratory that α-MSH, IGF-1, and TGF-β1 can downregulate IFN-γ–induced ectopic MHC class I expression in human anagen Hair bulbs in vitro . Finally, we suggest that Hair Follicle-derived α-MSH, IGF-γ, and TGF-β1 form part of a constitutively active "IP restoration machinery" of the anagen Hair bulb, which we propose to be recruited whenever the Hair Follicle suffers immune injury. Finally, we sketch some particularly promising avenues for future investigation into the far too long ignored Hair Follicle immune privilege.
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graying gerontobiology of the Hair Follicle pigmentary unit
Experimental Gerontology, 2001Co-Authors: Desmond J. Tobin, Ralf PausAbstract:Abstract The visual appearance of humans derives predominantly from their skin and Hair color. The phylogenetical pathway underling this phenomenon is called melanogenesis and results in the production of melanin pigments in neural crest-derived melanocytes, followed by its transfer to epithelial cells. While melanin from epidermal melanocytes clearly protects human skin by screening harmful ultraviolet radiation, the biologic value of Hair pigmentation is less clear. In addition to important roles in social/sexual communication, one potential benefit of pigmented scalp Hair in humans may be the rapid excretion of heavy metals, chemicals, toxins from the body by their selective binding to melanin. The Hair Follicle and epidermal melanogenic systems are broadly distinct, though open. The primary distinguishing feature of follicular melanogenesis, compared to the continuous melanogenesis in the epidermis, is the tight coupling of Hair Follicle melanogenesis to the Hair growth cycle. This cycle appears to involve periods of melanocyte proliferation (during early anagen), maturation (mid to late anagen) and melanocyte death via apoptosis (during early catagen). Thus, each Hair cycle is associated with the reconstruction of an intact Hair Follicle pigmentary unit… at least for the first 10 cycles or so. Thereafter, gray and white Hairs appear, suggesting an age-related, genetically regulated exhaustion of the pigmentary potential of each individual Hair Follicle. Melanocyte aging may be associated with reactive oxygen species-mediated damage to nuclear and mitochondrial DNA with resultant accumulation of mutations with age, in addition to dysregulation of anti-oxidant mechanisms or pro/anti-apoptotic factors within the cells. While the perception of “gray Hair” derives in large part from the admixture of pigmented and white Hair, it is important to note that individual Hair Follicles can indeed exhibit pigment dilution or true grayness. This dilution is due to a reduction in tyrosinase activity of Hair bulbar melanocytes, sub-optimal melanocyte–cortical keratinocyte interactions, and defective migration of melanocytes from a reservoir in the upper outer root sheath to the pigment-permitting microenvironment close to the dermal papilla of the Hair bulb. Animal models with mutations in apoptotic survival factors (e.g. bcl-2) and in melanogenic enzymes (TRP-1) are providing valuable insights into the aging Hair pigmentary unit. It is from these and other advances, including our ability to grow Hair Follicle melanocytes in vitro, that the possibility of reversing canities has been raised. Indeed, it is not too uncommon to see spontaneous repigmentation along the same individual Hair shaft in early canities. Moreover, melanocytes taken from gray and white Hair Follicles can be induced to pigment in vitro. One of the surprising results of pigment loss in canities is the alteration in keratinocyte proliferation and differentiation, providing the tantalizing suggestion that melanocytes in the Hair Follicle contribute far more that packages of melanin alone. Furthermore, there have been some unconfirmed reports in the literature suggesting that canities may link (although not causally) with more systemic alterations in homeostasis e.g. osteoporosis. Here, we review the current state of knowledge of the development, regulation and control of the human Hair Follicle pigmentary unit during life.
Desmond J. Tobin - One of the best experts on this subject based on the ideXlab platform.
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The cell biology of human Hair Follicle pigmentation
Pigment Cell & Melanoma Research, 2011Co-Authors: Desmond J. TobinAbstract:Although we have made significant progress in understanding the regulation of the UVR-exposed epidermal-melanin unit, we know relatively little about how human Hair Follicle pigmentation is regulated. Progress has been hampered by gaps in our knowledge of the Hair growth cycle's controls, to which Hair pigmentation appears tightly coupled. However, pigment cell researchers may have overly focused on the follicular melanocytes of the nocturnal and UVR-shy mouse as a proxy for human epidermal melanocytes. Here, I emphasize the epidermis-follicular melanocyte pluralism of human skin, as research models for vitiligo, alopecia areata and melanoma, personal care/cosmetics innovation. Further motivation could be in finding answers to why Hair Follicle and epidermal pigmentary units remain broadly distinct? Why melanomas tend to originate from epidermal rather than follicular melanocytes? Why multiple follicular melanocyte sub-populations exist? Why follicular melanocytes are more sensitive to aging influences? In this perspective, I attempt to raise the status of the human Hair Follicle melanocyte and highlight some species-specific issues involved which the general reader of the pigmentation literature (with its substantial mouse-based data) may not fully appreciate.
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Gerontobiology of the Hair Follicle
Aging Hair, 2010Co-Authors: Desmond J. TobinAbstract:The word “gerontology” is familiar to most of us as a term that captures the study of the social, psychological, and biological aspects of aging. However, its derivative “gerontobiology” as applied to the Hair Follicle is more concerned with the latter aspect – the biology of aging in the Hair Follicle mini-organ. As with any complex multicellular tissue system, the Hair Follicle is prone to broadly similar underlying processes that determine the functional longevity of organs and tissues. No matter how complex the tissue system is, it will contain cells that eventually lose functionality, reproductive potential and will ultimately die. The Hair Follicle is somewhat unusual among mammalian tissues in that it is a veritable histologic melange of multiple cell types (e.g., epithelial, mesenchymal and neuro-ectodermal) that function contemporaneously in all stages of their life histories e.g., stem cells, transit-amplifying cells, and terminally differentiating cells. Some of these interactive cell systems appear to be nonessential for overall Hair Follicle survival (e.g., melanocytes). However, strikingly graying Hair Follicles may grow even more vigorously than their pigmented predecessors. Moreover, the Hair Follicle is unique in the adult mammal in that it follows a tightly regulated script of multiple lifelong cycles of cellular birth, proliferation, differentiation, and death. Powerful evolutionary selection ensures that the Hair Follicle is, in the main, hardwired against significant aging-related loss of function, even after 12 or more decades of life – although some would argue with this view, if only on purely cosmetic grounds. Processes underlying aging in general, e.g., oxidative damage, telomere shortening, age-relating deficiencies related to nuclear/mitochondrial DNA damage and repair as well as age-related reductions in the cells’ energy supply, will all impact on whether some follicular cell subpopulations will enter cellular senescence. This chapter will focus on how gerontobiology of the Hair Follicle may impact on certain aspects of Hair fiber phenotype.
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Hair Follicle pigmentation
Journal of Investigative Dermatology, 2005Co-Authors: Andrzej Slominski, Ralf Paus, Jacobo Wortsman, Przemyslaw M Plonka, Karin U Schallreuter, Desmond J. TobinAbstract:Hair shaft melanin components (eu- or/and pheomelanin) are a long-lived record of precise interactions in the Hair Follicle pigmentary unit, e.g., between follicular melanocytes, keratinocytes, and dermal papilla fibroblasts. Follicular melanogenesis (FM) involves sequentially the melanogenic activity of follicular melanocytes, the transfer of melanin granules into cortical and medulla keratinocytes, and the formation of pigmented Hair shafts. This activity is in turn regulated by an array of enzymes, structural and regulatory proteins, transporters, and receptors and their ligands, acting on the developmental stages, cellular, and Hair Follicle levels. FM is stringently coupled to the anagen stage of the Hair cycle, being switched-off in catagen to remain absent through telogen. At the organ level FM is precisely coupled to the life cycle of melanocytes with changes in their compartmental distribution and accelerated melanoblast/melanocyte differentiation with enhanced secretory activity. The melanocyte compartments in the upper Hair Follicle also provides a reservoir for the repigmentation of epidermis and, for the cyclic formation of new anagen Hair bulbs. Melanin synthesis and pigment transfer to bulb keratinocytes are dependent on the availability of melanin precursors, and regulation by signal transduction pathways intrinsic to skin and Hair Follicle, which are both receptor dependent and independent, act through auto-, para- or intracrine mechanisms and can be modified by hormonal signals. The important regulators are MC1 receptor its and adrenocorticotropic hormone, melanocyte stimulating hormone, agouti protein ligands (in rodents), c-Kit, and the endothelin receptors with their ligands. Melanin itself has a wide range of bioactivities that extend far beyond its determination of Hair color.
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Characterization of Hair Follicle Antigens Targeted by the Anti-Hair Follicle Immune Response
Journal of Investigative Dermatology Symposium Proceedings, 2003Co-Authors: Desmond J. TobinAbstract:Alopecia areata is a common disfiguring Hair loss disorder that primarily affects the Hair Follicle as it enters the prolonged growth phase called anagen. The last few years have yielded an explosion of more rigorously obtained data on the etiology and pathogenesis of this disorder. While a consensus is rapidly building in support of an autoimmune pathogenesis, there are still several enigmatic issues to be resolved. These include the possibility that alopecia areata is really a multientity disorder with causes that are multifactorial. This will have important implications for the research scientist's search for the jigsaw puzzle's largest missing piece—the identification of the target autoantigen(s). There is now much evidence that autoimmune diseases with both T and B cell components have shared target autoantigens/epitopes. It is likely that alopecia areata is similar, as there is now very strong evidence for the generation of autoantibodies as well as autoreactive T cells to Hair Follicles in the pathogenesis of this disease. The following brief review outlines the progress we have made over the last five to ten years in the characterization of Hair Follicle antigens targeted by antibodies in alopecia areata. Results of these studies now show that the elicitation of antibodies to Hair Follicle–specific proteins is a highly conserved phenomenon in all affected species studied to date. Candidate autoantigens that have been identified include the 44/46 kDa Hair-specific keratin (expressed in the precortical zone of anagen Hair Follicles) and trichohyalin (an important intermediate filament–associated protein) expressed in the inner root sheath of the growing Hair Follicle. Moreover, there is evidence that anti-Hair Follicle antibodies are modulated during the disease process, can occur before clinically detectable Hair loss, and may be reduced in titer during successful treatment. Preliminary data from passive transfer experiments suggest that in some species these antibodies may disrupt Hair cycling. We are currently applying a more molecular approach (e.g., cDNA library screening) to identify Hair Follicle antigens truly associated with the onset of the disorder.
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graying gerontobiology of the Hair Follicle pigmentary unit
Experimental Gerontology, 2001Co-Authors: Desmond J. Tobin, Ralf PausAbstract:Abstract The visual appearance of humans derives predominantly from their skin and Hair color. The phylogenetical pathway underling this phenomenon is called melanogenesis and results in the production of melanin pigments in neural crest-derived melanocytes, followed by its transfer to epithelial cells. While melanin from epidermal melanocytes clearly protects human skin by screening harmful ultraviolet radiation, the biologic value of Hair pigmentation is less clear. In addition to important roles in social/sexual communication, one potential benefit of pigmented scalp Hair in humans may be the rapid excretion of heavy metals, chemicals, toxins from the body by their selective binding to melanin. The Hair Follicle and epidermal melanogenic systems are broadly distinct, though open. The primary distinguishing feature of follicular melanogenesis, compared to the continuous melanogenesis in the epidermis, is the tight coupling of Hair Follicle melanogenesis to the Hair growth cycle. This cycle appears to involve periods of melanocyte proliferation (during early anagen), maturation (mid to late anagen) and melanocyte death via apoptosis (during early catagen). Thus, each Hair cycle is associated with the reconstruction of an intact Hair Follicle pigmentary unit… at least for the first 10 cycles or so. Thereafter, gray and white Hairs appear, suggesting an age-related, genetically regulated exhaustion of the pigmentary potential of each individual Hair Follicle. Melanocyte aging may be associated with reactive oxygen species-mediated damage to nuclear and mitochondrial DNA with resultant accumulation of mutations with age, in addition to dysregulation of anti-oxidant mechanisms or pro/anti-apoptotic factors within the cells. While the perception of “gray Hair” derives in large part from the admixture of pigmented and white Hair, it is important to note that individual Hair Follicles can indeed exhibit pigment dilution or true grayness. This dilution is due to a reduction in tyrosinase activity of Hair bulbar melanocytes, sub-optimal melanocyte–cortical keratinocyte interactions, and defective migration of melanocytes from a reservoir in the upper outer root sheath to the pigment-permitting microenvironment close to the dermal papilla of the Hair bulb. Animal models with mutations in apoptotic survival factors (e.g. bcl-2) and in melanogenic enzymes (TRP-1) are providing valuable insights into the aging Hair pigmentary unit. It is from these and other advances, including our ability to grow Hair Follicle melanocytes in vitro, that the possibility of reversing canities has been raised. Indeed, it is not too uncommon to see spontaneous repigmentation along the same individual Hair shaft in early canities. Moreover, melanocytes taken from gray and white Hair Follicles can be induced to pigment in vitro. One of the surprising results of pigment loss in canities is the alteration in keratinocyte proliferation and differentiation, providing the tantalizing suggestion that melanocytes in the Hair Follicle contribute far more that packages of melanin alone. Furthermore, there have been some unconfirmed reports in the literature suggesting that canities may link (although not causally) with more systemic alterations in homeostasis e.g. osteoporosis. Here, we review the current state of knowledge of the development, regulation and control of the human Hair Follicle pigmentary unit during life.
Lingna Li - One of the best experts on this subject based on the ideXlab platform.
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Protocols for Cryopreservation of Intact Hair Follicle That Maintain Pluripotency of Nestin-Expressing Hair-Follicle-Associated Pluripotent (HAP) Stem Cells.
Methods of Molecular Biology, 2016Co-Authors: Satoshi Kajiura, Lingna Li, Robert M Hoffman, Yuko Hamada, Nobuko Arakawa, Katsumasa Kawahara, Kensei Katsuoka, Yasuyuki AmohAbstract:: Hair Follicles contain nestin-expressing pluripotent stem cells, the origin of which is above the bulge area, below the sebaceous gland. We have termed these cells Hair-Follicle-associated pluripotent (HAP) stem cells. Cryopreservation methods of the Hair Follicle that maintain the pluripotency of HAP stem cells are described in this chapter. Intact Hair Follicles from green fluorescent protein (GFP) transgenic mice were cryopreserved by slow-rate cooling in TC-Protector medium and storage in liquid nitrogen. After thawing, the upper part of the Hair Follicle was isolated and cultured in DMEM with fetal bovine serum (FBS). After 4 weeks culture, cells from the upper part of the Hair Follicles grew out. The growing cells were transferred to DMEM/F12 without FBS. After 1 week culture, the growing cells formed Hair spheres, each containing approximately 1 × 10(2) HAP stem cells. The Hair spheres contained cells which could differentiate to neurons, glial cells, and other cell types. The formation of Hair spheres by the thawed and cultured upper part of the Hair Follicle produced almost as many pluripotent Hair spheres as fresh Follicles. The Hair spheres derived from cryopreserved Hair Follicles were as pluripotent as Hair spheres from fresh Hair Follicles. These results suggest that the cryopreservation of the whole Hair Follicle is an effective way to store HAP stem cells for personalized regenerative medicine, enabling any individual to maintain a bank of pluripotent stem cells for future clinical use.
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Cryopreservation of the Hair Follicle Maintains Pluripotency of Nestin-Expressing Hair Follicle-Associated Pluripotent Stem Cells
Tissue Engineering Part C-methods, 2015Co-Authors: Satoshi Kajiura, Lingna Li, Robert M Hoffman, Yuko Hamada, Nobuko Arakawa, Katsumasa Kawahara, Kensei Katsuoka, Yasuyuki AmohAbstract:Hair Follicles contain nestin-expressing pluripotent stem cells, the origin of which is above the bulge area, below the sebaceous gland. We have termed these cells Hair Follicle-associated pluripotent (HAP) stem cells. In the present study, we established efficient cryopreservation methods of the Hair Follicle that maintained the pluripotency of HAP stem cells. We cryopreserved the whole Hair Follicle from green fluorescent protein transgenic mice by slow-rate cooling in TC-Protector medium and storage in liquid nitrogen. After thawing, the upper part of the Hair Follicle was isolated and cultured in Dulbecco's Modified Eagle's Medium (DMEM) with fetal bovine serum (FBS). After 4 weeks of culture, cells from the upper part of the Hair Follicle grew out. The growing cells were transferred to DMEM/F12 without FBS. After 1 week of culture, the growing cells formed Hair spheres, each containing ∼1×102 HAP stem cells. The Hair spheres contained cells that differentiated to neurons, glial cells, and other cell ...
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nestin expression in Hair Follicle sheath progenitor cells
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Lingna Li, Grigori Enikolopov, John Mignone, Maja Matic, Sheldon Penman, Meng Yang, Robert M HoffmanAbstract:The intermediate filament protein, nestin, marks progenitor cells of the CNS. Such CNS stem cells are selectively labeled by placing GFP under the control of the nestin regulatory sequences. During early anagen or growth phase of the Hair Follicle, nestin-expressing cells, marked by GFP fluorescence in nestin-GFP transgenic mice, appear in the permanent upper Hair Follicle immediately below the sebaceous glands in the Follicle bulge. This is where stem cells for the Hair Follicle outer-root sheath are thought to be located. The relatively small, oval-shaped, nestin-expressing cells in the bulge area surround the Hair shaft and are interconnected by short dendrites. The precise locations of the nestin-expressing cells in the Hair Follicle vary with the Hair cycle. During telogen or resting phase and in early anagen, the GFP-positive cells are mainly in the bulge area. However, in mid- and late anagen, the GFP-expressing cells are located in the upper outer-root sheath as well as in the bulge area but not in the Hair matrix bulb. These observations show that the nestin-expressing cells form the outer-root sheath. Results of the immunohistochemical staining showed that nestin, GFP, keratin 5/8, and keratin 15 colocalize in the Hair Follicle bulge cells, outer-root sheath cells, and basal cells of the sebaceous glands. These data indicate that nestin-expressing cells, marked by GFP, in the Hair Follicle bulge are indeed progenitors of the Follicle outer-root sheath. The expression of the unique protein, nestin, in both neural stem cells and Hair Follicle stem cells suggests their possible relation.
