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The Journal of Investigative... Dec 1999Hair follicle (HF) morphogenesis and cycling are characterized by a tightly controlled balance of proliferation, differentiation and apoptosis. The members of the bcl-2... (Review)
Review
Hair follicle (HF) morphogenesis and cycling are characterized by a tightly controlled balance of proliferation, differentiation and apoptosis. The members of the bcl-2 family of proto-oncogenes are important key players in the apoptosis control machinery of most cell types. Bcl-2, an apoptosis inhibitor, and Bax, an apoptosis promoter, show tightly regulated, hair cycle-dependent expression patterns: during catagen, the distal ORS of the HF remains strongly positive for Bcl-2 and Bax; in contrast, the proximal epithelial part of the HF loses most Bcl-2 expression while it remains strongly positive for Bax. In Bcl-2 null mice, skin becomes markedly hypopigmented during the first postnatal anagen probably due to increased melanocyte apoptosis. Reportedly, these mice also show a retardation of the first anagen development after birth. Transgenic mice overexpressing Bcl-2 under the control of the keratin-1 promoter display multifocal epidermal hyperplasia and aberrant expression of keratin-6, while alterations of HF cycling have not been investigated. Surprisingly, Bcl-2 overexpression under the control of the keratin-14 promoter leads to accelerated catagen progression and increased chemotherapy-induced apoptosis, HF dystrophy and alopecia. Transgenic mice overexpressing Bcl-X(L), another anti-apoptotic bcl-2 family member, under the control of the K14 promoter, reportedly also display accelerated catagen development. These and other Bcl-2 transgenic and null mice are now available to further dissect the as yet unclear, and likely complex, role of Bcl-2 in HF growth and pigmentation.
Topics: Animals; Apoptosis; Gene Expression Regulation; Genes, bcl-2; Hair Follicle; Mice; Mice, Knockout; Mice, Transgenic; Proto-Oncogene Proteins c-bcl-2
PubMed: 10674380
DOI: 10.1038/sj.jidsp.5640228 -
Trends in Endocrinology and Metabolism:... Feb 2019Hair follicles (HFs) strongly interact with adipocytes within the dermal white adipose tissue (dWAT), suggesting a strong physiological dependence on the content of... (Review)
Review
Hair follicles (HFs) strongly interact with adipocytes within the dermal white adipose tissue (dWAT), suggesting a strong physiological dependence on the content of immature and mature adipocytes in this layer. This content is regulated by the proliferation and differentiation of adipocyte precursors, as well as by dedifferentiation of mature existing adipocytes. Spatially, long-range interactions between HFs and dWAT involve the exchange of extracellular vesicles which are differentially released by precursors, preadipocytes, and mature adipocytes. Different exogenous factors, including light irradiation, are likely to modify the release of adipocyte-derived exosomes in dWAT, which can lead to aberrations of the HF cycle. Consequently, dWAT should be considered as a potential target for the modulation of hair growth.
Topics: Adipocytes; Adipose Tissue, White; Animals; Cell Differentiation; Cell Proliferation; Hair Follicle; Humans
PubMed: 30558832
DOI: 10.1016/j.tem.2018.11.004 -
The Journal of Investigative... Oct 2003This essay reviews the available evidence that the proximal hair follicle epithelium generates and maintains an area of relative immune privilege during a defined... (Review)
Review
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 alpha-MSH and TGF-beta1. 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 alpha-MSH, IGF-1, and TGF-beta1 can downregulate IFN-gamma-induced ectopic MHC class I expression in human anagen hair bulbs in vitro. Finally, we suggest that hair follicle-derived alpha-MSH, IGF-gamma, and TGF-beta1 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.
Topics: Animals; Hair Follicle; Histocompatibility Antigens Class I; Humans; Immune Tolerance; Insulin-Like Growth Factor I; Transforming Growth Factor beta; Transforming Growth Factor beta1; alpha-MSH
PubMed: 14582671
DOI: 10.1046/j.1087-0024.2003.00807.x -
Stem Cells (Dayton, Ohio) Feb 2020Adult hair follicles undergo repeated cycling of regression (catagen), resting (telogen), and growth (anagen), which is maintained by hair follicle stem cells (HFSCs)....
Adult hair follicles undergo repeated cycling of regression (catagen), resting (telogen), and growth (anagen), which is maintained by hair follicle stem cells (HFSCs). The mechanism underlying hair growth initiation and HFSC maintenance is not fully understood. Here, by epithelial deletion of Hes1, a major Notch downstream transcriptional repressor, we found that hair growth is retarded, but the hair cycle progresses normally. Hes1 is specifically upregulated in the lower bulge/HG during anagen initiation. Accordingly, loss of Hes1 results in delayed activation of the secondary hair germ (HG) and shortened anagen phase. This developmental delay causes reduced hair shaft length but not identity changes in follicular lineages. Remarkably, Hes1 ablation results in impaired hair regeneration upon repetitive depilation. Microarray gene profiling on HFSCs indicates that Hes1 modulates Shh responsiveness in anagen initiation. Using primary keratinocyte cultures, we demonstrated that Hes1 deletion negatively influences ciliogenesis and Smoothened ciliary accumulation upon Shh treatment. Furthermore, transient application of Smoothened agonist during repetitive depilation can rescue anagen initiation and HFSC self-renewal in Hes1-deficient hair follicles. We reveal a critical function of Hes1 in potentiating Shh signaling in anagen initiation, which allows sufficient signaling strength to expand the HG and replenish HFSCs to maintain the hair cycle homeostasis.
Topics: Animals; Antigens; Hair Follicle; Hedgehog Proteins; Humans; Intermediate Filament Proteins; Mice; Signal Transduction; Stem Cells; Transcription Factor HES-1
PubMed: 31721388
DOI: 10.1002/stem.3117 -
Current Opinion in Cell Biology Dec 2020The mammalian skin is equipped with a highly dynamic stratified epithelium. The maintenance and regeneration of this epithelium is supported by basally located... (Review)
Review
The mammalian skin is equipped with a highly dynamic stratified epithelium. The maintenance and regeneration of this epithelium is supported by basally located keratinocytes, which display stem cell properties, including lifelong proliferative potential and the ability to undergo diverse differentiation trajectories. Keratinocytes support not just the surface of the skin, called the epidermis, but also a range of ectodermal structures including hair follicles, sebaceous glands, and sweat glands. Recent studies have shed light on the hitherto underappreciated heterogeneity of keratinocytes by employing state-of-the-art imaging technologies and single-cell genomic approaches. In this mini review, we highlight major recent discoveries that illuminate the dynamics and cellular mechanisms that govern keratinocyte differentiation in the live mammalian skin and discuss the broader implications of these findings for our understanding of epithelial and stem cell biology in general.
Topics: Animals; Cell Differentiation; Epidermal Cells; Hair Follicle; Humans; Keratinocytes; Models, Biological; Stem Cells
PubMed: 33091828
DOI: 10.1016/j.ceb.2020.09.004 -
The Journal of Investigative... Jan 2018The collapse of the immune privilege (IP) of the anagen hair bulb is now accepted as a key element in AA pathogenesis, and hair bulb IP restoration lies at the core of... (Review)
Review
The collapse of the immune privilege (IP) of the anagen hair bulb is now accepted as a key element in AA pathogenesis, and hair bulb IP restoration lies at the core of AA therapy. Here, we briefly review the essentials of hair bulb IP and recent progress in understanding its complexity. We discuss open questions and why the systematic dissection of hair bulb IP and its pharmacological manipulation (including the clinical testing of FK506 and α-melanocyte-stimulating hormone analogs) promise to extend the range of future therapeutic options in AA and other IP collapse-related autoimmune diseases.
Topics: Alopecia Areata; Autoimmune Diseases; Hair Follicle; Humans; Immune Privilege; Phenotype
PubMed: 29273098
DOI: 10.1016/j.jisp.2017.10.014 -
Current Topics in Developmental Biology 2016Frizzled proteins are the principal receptors for the Wnt family of ligands. They mediate canonical Wnt signaling together with Lrp5 and Lrp6 coreceptors. In conjunction... (Review)
Review
Frizzled proteins are the principal receptors for the Wnt family of ligands. They mediate canonical Wnt signaling together with Lrp5 and Lrp6 coreceptors. In conjunction with Celsr, Vangl, and a small number of additional membrane and membrane-associated proteins, they also play a central role in tissue polarity/planar cell polarity (PCP) signaling. Targeted mutations in 9 of the 10 mammalian Frizzled genes have revealed their roles in an extraordinarily diverse set of developmental and homeostatic processes, including morphogenetic movements responsible for palate, ventricular septum, ocular furrow, and neural tube closure; survival of thalamic neurons; bone formation; central nervous system (CNS) angiogenesis and blood-brain barrier formation and maintenance; and a wide variety of processes that orient subcellular, cellular, and multicellular structures relative to the body axes. The last group likely reflects the mammalian equivalent of tissue polarity/PCP signaling, as defined in Drosophila, and it includes CNS axon guidance, hair follicle and tongue papilla orientation, and inner ear sensory hair bundle orientation. Frizzled receptors are ubiquitous among multicellular animals and, with other signaling molecules, they very likely evolved to permit the development of the complex tissue architectures that provide multicellular animals with their enormous selective advantage.
Topics: Animals; Cell Polarity; Disease; Frizzled Receptors; Hair Follicle; Humans; Neurons; Signal Transduction
PubMed: 26969975
DOI: 10.1016/bs.ctdb.2015.11.028 -
The Journal of Investigative Dermatology Aug 2022Fzd2 is required for hair follicle function and maintenance in mice.
Fzd2 is required for hair follicle function and maintenance in mice.
Topics: Animals; Hair Follicle; Mice
PubMed: 35051380
DOI: 10.1016/j.jid.2022.01.004 -
Seminars in Cell & Developmental Biology 2014Hair follicles are appendages of the mammalian skin that have the ability to periodically and stereotypically regenerate in order to continuously produce new hair over... (Review)
Review
Hair follicles are appendages of the mammalian skin that have the ability to periodically and stereotypically regenerate in order to continuously produce new hair over our lifetime. The ability of the hair follicle to regenerate is due to the presence of stem cells that along with other cell populations and non-cellular components, including molecular signals and extracellular material, make up a niche microenvironment. Mounting evidence suggests that the niche is critical for regulating stem cell behavior and thus the process of regeneration. Here, we review the literature concerning past and current studies that have utilized mouse genetic models, combined with other approaches to dissect the molecular and cellular composition of the hair follicle niche. We also discuss our current understanding of how stem cells operate within the niche during the process of tissue regeneration and the factors that regulate their behavior.
Topics: Animals; Hair Follicle; Humans; Mice; Regeneration; Stem Cell Niche
PubMed: 24361866
DOI: 10.1016/j.semcdb.2013.12.005 -
The Journal of Clinical Investigation Feb 2012The adult hair follicle houses stem cells that govern the cyclical growth and differentiation of multiple cell types that collectively produce a pigmented hair. Recent... (Review)
Review
The adult hair follicle houses stem cells that govern the cyclical growth and differentiation of multiple cell types that collectively produce a pigmented hair. Recent studies have revealed that hair follicle stem cells are heterogeneous and dynamic throughout the hair cycle. Moreover, interactions between heterologous stem cells, including both epithelial and melanocyte stem cells, within the hair follicle are just now being explored. This review will describe how recent findings have expanded our understanding of the development, organization, and regeneration of hair follicle stem cells. At a basic level, this review is intended to help construct a reference point to integrate the surge of studies on the molecular mechanisms that regulate these cells.
Topics: Animals; Hair Follicle; Humans; Melanocytes; Regeneration; Stem Cell Niche; Stem Cells
PubMed: 22293183
DOI: 10.1172/JCI57414