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Fiona M Watt - One of the best experts on this subject based on the ideXlab platform.
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the Interfollicular Epidermis of adult mouse tail comprises two distinct cell lineages that are differentially regulated by wnt edaradd and lrig1
Stem cell reports, 2013Co-Authors: Celine Gomez, Denis J. Headon, Wesley Chua, Ahmad Miremadi, Sven R Quist, Fiona M WattAbstract:Current models of how mouse tail Interfollicular Epidermis (IFE) is maintained overlook the coexistence of two distinct terminal differentiation programs: parakeratotic (scale) and orthokeratotic (interscale). Lineage tracing and clonal analysis revealed that scale and interscale are maintained by unipotent cells in the underlying basal layer, with scale progenitors dividing more rapidly than interscale progenitors. Although scales are pigmented and precisely aligned with hair follicles, melanocytes and follicles were not necessary for scale differentiation. Epidermal Wnt signaling was required for scale enlargement during development and for postnatal maintenance of scale-interscale boundaries. Loss of Edaradd inhibited ventral scale formation, whereas loss of Lrig1 led to scale enlargement and fusion. In wild-type skin, Lrig1 was not expressed in IFE but was selectively upregulated in dermal fibroblasts underlying the interscale. We conclude that the different IFE differentiation compartments are maintained by distinct stem cell populations and are regulated by epidermal and dermal signals.
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lrig1 expression defines a distinct multipotent stem cell population in mammalian Epidermis
Cell Stem Cell, 2009Co-Authors: Kim B Jensen, Charlotte A Collins, Elisabete Nascimento, David W M Tan, Michaela Frye, Satoshi Itami, Fiona M WattAbstract:Lrig1 is a marker of human Interfollicular epidermal stem cells and helps maintain stem cell quiescence. We show that, in mouse Epidermis, Lrig1 defines the hair follicle junctional zone adjacent to the sebaceous glands and infundibulum. Lrig1 is a Myc target gene; loss of Lrig1 increases the proliferative capacity of stem cells in culture and results in epidermal hyperproliferation in vivo. Lrig1-expressing cells can give rise to all of the adult epidermal lineages in skin reconstitution assays. However, during homeostasis and on retinoic acid stimulation, they are bipotent, contributing to the sebaceous gland and Interfollicular Epidermis. β-catenin activation increases the size of the junctional zone compartment, and loss of Lrig1 causes a selective increase in β-catenin-induced ectopic hair follicle formation in the Interfollicular Epidermis. Our results suggest that Lrig1-positive cells constitute a previously unidentified reservoir of adult mouse Interfollicular epidermal stem cells.
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Epidermal stem cells are defined by global histone modifications that are altered by Myc-induced differentiation
PloS one, 2007Co-Authors: Michaela Frye, Amanda G. Fisher, Fiona M WattAbstract:Activation of Myc induces epidermal stem cells to exit their niche and differentiate into sebocytes and Interfollicular Epidermis, a process that is associated with widespread changes in gene transcription. We have identified chromatin modifications that are characteristic of epidermal stem cells and investigated the effects of Myc activation. Quiescent stem cells in the Interfollicular Epidermis and the hair follicle bulge had high levels of tri-methylated histone H3 at lysine 9 and H4 at lysine 20. Chromatin in both stem cell populations was hypoacteylated at histone H4 and lacked mono-methylation of histone H4 at lysine 20. Myc-induced exit from the stem cell niche correlated with increased acetylation at histone H4 and transiently increased mono-methylation at lysine 20. The latter was replaced by epigenetic modifications that are largely associated with chromatin silencing: di-methylation at histone H3 lysine 9 and histone H4 lysine 20. These modifications correlated with changes in the specific histone methyltransferases Set8 and Ash-1. The Myc-induced switch from mono- to di-methylated H4K20 required HDAC activity and was blocked by the HDAC inhibitor trichostatin A (TSA). TSA treatment induced a similar epidermal phenotype to activation of Myc, and activation of Myc in the presence of TSA resulted in massive stimulation of terminal differentiation. We conclude that Myc-induced chromatin modifications play a major role in Myc-induced exit from the stem cell compartment.
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Syntenin mediates Delta1-induced cohesiveness of epidermal stem cells in culture
Journal of Cell Science, 2007Co-Authors: Soline Estrach, James Legg, Fiona M WattAbstract:In human Interfollicular Epidermis, stem cell clusters express high levels of the Notch ligand Delta1. Delta1 stimulates neighbouring cells to differentiate and also promotes stem cell clustering. Although Notch signalling is known to stimulate epidermal differentiation, little is known about the mechanism by which Delta1 promotes epidermal cell cohesiveness. This is an important issue, because the location of stem cells determines the local microenvironmental signals they receive. We now show that mutation of the Delta1 PDZ-binding domain abolishes Delta1-mediated keratinocyte cohesiveness, stimulates Notch transcriptional activity and promotes epidermal differentiation. A yeast two-hybrid screen revealed that Delta1 binds to the adaptor protein syntenin – an interaction dependent on the Delta1 PDZ-binding domain. Syntenin, like Delta1, is upregulated in the stem cell clusters of human Interfollicular Epidermis. Knockdown of syntenin in cells overexpressing full-length Delta1 had the same effects on Notch signalling, epidermal differentiation and adhesion as overexpressing Delta1 with a mutated PDZ-binding domain. Syntenin has previously been reported to regulate membrane traffic, and mutation of the Delta1 PDZ-binding domain or knockdown of syntenin led to rapid internalisation of Delta1. We propose that syntenin binding to Delta1 plays a dual role in promoting intercellular adhesion and regulating Notch signalling.
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β catenin and hedgehog signal strength can specify number and location of hair follicles in adult Epidermis without recruitment of bulge stem cells
Developmental Cell, 2005Co-Authors: Violeta Silvavargas, Kristin M Braun, Cristina Lo Celso, Adam Giangreco, Tyler Ofstad, David M Prowse, Fiona M WattAbstract:Summary Using K14ΔNβ-cateninER transgenic mice, we show that short-term, low-level β-catenin activation stimulates de novo hair follicle formation from sebaceous glands and Interfollicular Epidermis, while only sustained, high-level activation induces new follicles from preexisting follicles. The Hedgehog pathway is upregulated by β-catenin activation, and inhibition of Hedgehog signaling converts the low β-catenin phenotype to wild-type Epidermis and the high phenotype to low. β-catenin-induced follicles contain clonogenic keratinocytes that express bulge markers; the follicles induce dermal papillae and provide a niche for melanocytes, and they undergo 4OHT-dependent cycles of growth and regression. New follicles induced in Interfollicular Epidermis are derived from that cellular compartment and not through bulge stem cell migration or division. These results demonstrate the remarkable capacity of adult Epidermis to be reprogrammed by titrating β-catenin and Hedgehog signal strength and establish that cells from Interfollicular Epidermis can acquire certain characteristics of bulge stem cells.
Catherin Niemann - One of the best experts on this subject based on the ideXlab platform.
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Human skin stem cells and the ageing process
Experimental gerontology, 2008Co-Authors: C. C. Zouboulis, James Adjaye, Hirohiko Akamatsu, Gerd Moe-behrens, Catherin NiemannAbstract:In healthy individuals, skin integrity is maintained by epidermal stem cells which self-renew and generate daughter cells that undergo terminal differentiation. Despite accumulation of senescence markers in aged skin, epidermal stem cells are maintained at normal levels throughout life. Therefore, skin ageing is induced by impaired stem cell mobilisation or reduced number of stem cells able to respond to proliferative signals. In the skin, existence of several distinct stem cell populations has been reported. Genetic labelling studies detected multipotent stem cells of the hair follicle bulge to support regeneration of hair follicles but not been responsible for maintaining Interfollicular Epidermis, which exhibits a distinct stem cell population. Hair follicle epithelial stem cells have at least a dual function: hair follicle remodelling in daily life and epidermal regeneration whenever skin integrity is severely compromised, e.g. after burns. Bulge cells, the first adult stem cells of the hair follicle been identified, are capable of forming hair follicles, Interfollicular Epidermis and sebaceous glands. In addition, -- at least in murine hair follicles -- they can also give rise to non-epithelial cells, indicating a lineage-independent pluripotent character. Multipotent cells (skin-derived precursor cells) are present in human dermis; dermal stem cells represent 0.3% among human dermal foreskin fibroblasts. A resident pool of progenitor cells exists within the sebaceous gland, which is able to differentiate into both sebocytes and Interfollicular Epidermis. The self-renewal and multi-lineage differentiation of skin stem cells make these cells attractive for ageing process studies but also for regenerative medicine, tissue repair, gene therapy and cell-based therapy with autologous adult stem cells not only in dermatology. In addition, they provide in vitro models to study epidermal lineage selection and its role in the ageing process.
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manipulation of stem cell proliferation and lineage commitment visualisation of label retaining cells in wholemounts of mouse Epidermis
Development, 2003Co-Authors: Kristin M Braun, Catherin Niemann, Violeta Silvavargas, John P Sundberg, Uffe Birk Jensen, Fiona M WattAbstract:Mammalian Epidermis is maintained by stem cells that have the ability to self-renew and generate daughter cells that differentiate along the lineages of the hair follicles, Interfollicular Epidermis and sebaceous gland. As stem cells divide infrequently in adult mouse Epidermis, they can be visualised as DNA label-retaining cells (LRC). With whole-mount labelling, we can examine large areas of Interfollicular Epidermis and many hair follicles simultaneously, enabling us to evaluate stem cell markers and examine the effects of different stimuli on the LRC population. LRC are not confined to the hair follicle, but also lie in sebaceous glands and Interfollicular Epidermis. LRC reside throughout the permanent region of the hair follicle, where they express keratin 15 and lie in a region of high α6β4 integrin expression. LRC are not significantly depleted by successive hair growth cycles. They can, nevertheless, be stimulated to divide by treatment with phorbol ester, resulting in near complete loss of LRC within 12 days. Activation of Myc stimulates epidermal proliferation without depleting LRC and induces differentiation of sebocytes within the Interfollicular Epidermis. Expression of N-terminally truncated Lef1 to block β-catenin signalling induces transdifferentiation of hair follicles into Interfollicular Epidermis and sebocytes and causes loss of LRC primarily through proliferation. We conclude that LRC are more sensitive to some proliferative stimuli than others and that changes in lineage can occur with or without recruitment of LRC into cycle.
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expression of δnlef1 in mouse Epidermis results in differentiation of hair follicles into squamous epidermal cysts and formation of skin tumours
Development, 2002Co-Authors: Catherin Niemann, David M. Owens, Jorg Hulsken, Walter Birchmeier, Fiona M WattAbstract:To examine the consequences of repressing β-catenin/Lef1 signalling in mouse Epidermis, we expressed a ΔNLef1 transgene, which lacks the β-catenin binding site, under the control of the keratin 14 promoter. No skin abnormalities were detected before the first postnatal hair cycle. However, from 6 weeks of age, mice underwent progressive hair loss which correlated with the development of dermal cysts. The cysts were derived from the base of the hair follicles and expressed morphological and molecular markers of Interfollicular Epidermis. Adult mice developed spontaneous skin tumours, most of which exhibited sebaceous differentiation, which could be indicative of an origin in the upper part of the hair follicle. The transgene continued to be expressed in the tumours and β-catenin signalling was still inhibited, as evidenced by absence of cyclin D1 expression. However, patched mRNA expression was upregulated, suggesting that the sonic hedgehog pathway might play a role in tumour formation. Based on our results and previous data on the consequences of activating β-catenin/Lef1 signalling in postnatal keratinocytes, we conclude that the level of β-catenin signalling determines whether keratinocytes differentiate into hair or Interfollicular Epidermis, and that perturbation of the pathway by overexpression of ΔNLef1 can lead to skin tumour formation.
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Expression of ΔNLef1 in mouse Epidermis results in differentiation of hair follicles into squamous epidermal cysts and formation of skin tumours
Development (Cambridge England), 2002Co-Authors: Catherin Niemann, David M. Owens, Jorg Hulsken, Walter Birchmeier, Fiona M WattAbstract:To examine the consequences of repressing beta-catenin/Lef1 signalling in mouse Epidermis, we expressed a DeltaNLef1 transgene, which lacks the beta-catenin binding site, under the control of the keratin 14 promoter. No skin abnormalities were detected before the first postnatal hair cycle. However, from 6 weeks of age, mice underwent progressive hair loss which correlated with the development of dermal cysts. The cysts were derived from the base of the hair follicles and expressed morphological and molecular markers of Interfollicular Epidermis. Adult mice developed spontaneous skin tumours, most of which exhibited sebaceous differentiation, which could be indicative of an origin in the upper part of the hair follicle. The transgene continued to be expressed in the tumours and beta-catenin signalling was still inhibited, as evidenced by absence of cyclin D1 expression. However, patched mRNA expression was upregulated, suggesting that the sonic hedgehog pathway might play a role in tumour formation. Based on our results and previous data on the consequences of activating beta-catenin/Lef1 signalling in postnatal keratinocytes, we conclude that the level of beta-catenin signalling determines whether keratinocytes differentiate into hair or Interfollicular Epidermis, and that perturbation of the pathway by overexpression of DeltaNLef1 can lead to skin tumour formation.
David M. Owens - One of the best experts on this subject based on the ideXlab platform.
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Constitutive transgene expression of Stem Cell Antigen-1 in the hair follicle alters the sensitivity to tumor formation and progression
Stem cell research, 2017Co-Authors: Rikke Christensen, David M. Owens, Annette Füchtbauer, Anders Gunnarsson, Mette Ramsing, Ernst-martin Füchtbauer, Uffe Birk JensenAbstract:The cell surface protein Stem Cell Antigen-1 (Sca-1) marks stem or progenitor cells in several murine tissues and is normally upregulated during cancer development. Although the specific function of Sca-1 remains unknown, Sca-1 seems to play a role in proliferation, differentiation and cell migration in a number of tissues. In the skin epithelium, Sca-1 is highly expressed in the Interfollicular Epidermis but is absent in most compartments of the hair follicle; however, the function of Sca-1 in the skin has not been investigated. To explore the role of Sca-1 in normal and malignant skin development we generated transgenic mice that express Sca-1 in the hair follicle stem cells that are normally Sca-1 negative. Development of hair follicles and Interfollicular Epidermis appeared normal in Sca-1 mutant mice; however, follicular induction of Sca-1 expression in bulge region and isthmus stem cells reduced the overall yield of papillomas in a chemical carcinogenesis protocol. Despite that fewer papillomas developed in transgenic mice a higher proportion of the papillomas underwent malignant conversion. These findings suggest that overexpression of Sca-1 in the hair follicle stem cells contributes at different stages of tumour development. In early stages, overexpression of Sca-1 decreases tumour formation while at later stages overexpression of Sca-1 seems to drive tumours towards malignant progression.
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The Skin: A Home to Multiple Classes of Epithelial Progenitor Cells
Stem Cell Reviews, 2008Co-Authors: David M. OwensAbstract:To maintain homeostasis in the adult skin, epithelial keratinocyte stem cells are thought to divide infrequently giving rise to short-lived (transit amplifying) cells that undergo a limited number of cell divisions and ultimately terminal differentiation. This model for the epidermal stem cell niche has increased in complexity by the multiple putative progenitor keratinocyte populations that have recently been identified in distinct regions of the Interfollicular Epidermis and hair follicle appendages. Under normal conditions, these progenitor populations are long-lived and able to sustain the cellular input to certain epidermal structures including the Interfollicular Epidermis and sebaceous gland. Other putative epithelial progenitors derived from the hair follicle possess high in vitro proliferative capacity and are able to regenerate skin, hair and sebaceous lineages in transplantation studies. These new findings present the cutaneous epithelium as a highly compartmentalized structure potentially maintained by multiple classes of progenitor cells. In this review, we will discuss the implications of these new putative epithelial progenitor populations and their potential to be influenced by external stimuli for skin homeostasis and carcinogenesis.
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expression of δnlef1 in mouse Epidermis results in differentiation of hair follicles into squamous epidermal cysts and formation of skin tumours
Development, 2002Co-Authors: Catherin Niemann, David M. Owens, Jorg Hulsken, Walter Birchmeier, Fiona M WattAbstract:To examine the consequences of repressing β-catenin/Lef1 signalling in mouse Epidermis, we expressed a ΔNLef1 transgene, which lacks the β-catenin binding site, under the control of the keratin 14 promoter. No skin abnormalities were detected before the first postnatal hair cycle. However, from 6 weeks of age, mice underwent progressive hair loss which correlated with the development of dermal cysts. The cysts were derived from the base of the hair follicles and expressed morphological and molecular markers of Interfollicular Epidermis. Adult mice developed spontaneous skin tumours, most of which exhibited sebaceous differentiation, which could be indicative of an origin in the upper part of the hair follicle. The transgene continued to be expressed in the tumours and β-catenin signalling was still inhibited, as evidenced by absence of cyclin D1 expression. However, patched mRNA expression was upregulated, suggesting that the sonic hedgehog pathway might play a role in tumour formation. Based on our results and previous data on the consequences of activating β-catenin/Lef1 signalling in postnatal keratinocytes, we conclude that the level of β-catenin signalling determines whether keratinocytes differentiate into hair or Interfollicular Epidermis, and that perturbation of the pathway by overexpression of ΔNLef1 can lead to skin tumour formation.
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Expression of ΔNLef1 in mouse Epidermis results in differentiation of hair follicles into squamous epidermal cysts and formation of skin tumours
Development (Cambridge England), 2002Co-Authors: Catherin Niemann, David M. Owens, Jorg Hulsken, Walter Birchmeier, Fiona M WattAbstract:To examine the consequences of repressing beta-catenin/Lef1 signalling in mouse Epidermis, we expressed a DeltaNLef1 transgene, which lacks the beta-catenin binding site, under the control of the keratin 14 promoter. No skin abnormalities were detected before the first postnatal hair cycle. However, from 6 weeks of age, mice underwent progressive hair loss which correlated with the development of dermal cysts. The cysts were derived from the base of the hair follicles and expressed morphological and molecular markers of Interfollicular Epidermis. Adult mice developed spontaneous skin tumours, most of which exhibited sebaceous differentiation, which could be indicative of an origin in the upper part of the hair follicle. The transgene continued to be expressed in the tumours and beta-catenin signalling was still inhibited, as evidenced by absence of cyclin D1 expression. However, patched mRNA expression was upregulated, suggesting that the sonic hedgehog pathway might play a role in tumour formation. Based on our results and previous data on the consequences of activating beta-catenin/Lef1 signalling in postnatal keratinocytes, we conclude that the level of beta-catenin signalling determines whether keratinocytes differentiate into hair or Interfollicular Epidermis, and that perturbation of the pathway by overexpression of DeltaNLef1 can lead to skin tumour formation.
Johanna M Brandner - One of the best experts on this subject based on the ideXlab platform.
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the role of tight junctions in skin barrier function and dermal absorption
Journal of Controlled Release, 2016Co-Authors: Katja Basler, Sophia Bergmann, Michael Heisig, Arne Naegel, Michaela Zornkruppa, Johanna M BrandnerAbstract:The skin protects our body from external assaults like pathogens, xenobiotics or UV irradiation. In addition, it prevents the loss of water and solutes. To fulfill these important tasks, a complex barrier system has developed which comprises the stratum corneum, tight junctions, the microbiome, the chemical barrier and the immunological barrier. These barriers do not act separately, but influence each other e.g. after external manipulation or in skin diseases. Especially the two mechanical barriers, i.e. stratum corneum and tight junctions, are of great interest for drug delivery, because they are the first interaction partners of drug delivery systems and play the major role in skin absorption. Tight junctions are of special interest, as they are centrally localized in this complex barrier system in the outermost viable layer - the stratum granulosum of the Interfollicular Epidermis and the companion cell layer of the hair follicle - and because they can react very quickly to stimuli. We summarize here our current knowledge about tight junction barrier function in mammalian Interfollicular Epidermis and hair follicles, and the interaction of tight junctions with other skin barrier components in health and disease. Furthermore, we discuss their relevance for drug delivery and provide examples for tight junction modulators.
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the role of tight junctions in skin barrier function and dermal absorption
Journal of Controlled Release, 2016Co-Authors: Katja Basler, Sophia Bergmann, Michael Heisig, Arne Naegel, Michaela Zornkruppa, Johanna M BrandnerAbstract:The skin protects our body from external assaults like pathogens, xenobiotics or UV irradiation. In addition, it prevents the loss of water and solutes. To fulfill these important tasks, a complex barrier system has developed which comprises the stratum corneum, tight junctions, the microbiome, the chemical barrier and the immunological barrier. These barriers do not act separately, but influence each other e.g. after external manipulation or in skin diseases. Especially the two mechanical barriers, i.e. stratum corneum and tight junctions, are of great interest for drug delivery, because they are the first interaction partners of drug delivery systems and play the major role in skin absorption. Tight junctions are of special interest, as they are centrally localized in this complex barrier system in the outermost viable layer - the stratum granulosum of the Interfollicular Epidermis and the companion cell layer of the hair follicle - and because they can react very quickly to stimuli. We summarize here our current knowledge about tight junction barrier function in mammalian Interfollicular Epidermis and hair follicles, and the interaction of tight junctions with other skin barrier components in health and disease. Furthermore, we discuss their relevance for drug delivery and provide examples for tight junction modulators.
Jorg Hulsken - One of the best experts on this subject based on the ideXlab platform.
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expression of δnlef1 in mouse Epidermis results in differentiation of hair follicles into squamous epidermal cysts and formation of skin tumours
Development, 2002Co-Authors: Catherin Niemann, David M. Owens, Jorg Hulsken, Walter Birchmeier, Fiona M WattAbstract:To examine the consequences of repressing β-catenin/Lef1 signalling in mouse Epidermis, we expressed a ΔNLef1 transgene, which lacks the β-catenin binding site, under the control of the keratin 14 promoter. No skin abnormalities were detected before the first postnatal hair cycle. However, from 6 weeks of age, mice underwent progressive hair loss which correlated with the development of dermal cysts. The cysts were derived from the base of the hair follicles and expressed morphological and molecular markers of Interfollicular Epidermis. Adult mice developed spontaneous skin tumours, most of which exhibited sebaceous differentiation, which could be indicative of an origin in the upper part of the hair follicle. The transgene continued to be expressed in the tumours and β-catenin signalling was still inhibited, as evidenced by absence of cyclin D1 expression. However, patched mRNA expression was upregulated, suggesting that the sonic hedgehog pathway might play a role in tumour formation. Based on our results and previous data on the consequences of activating β-catenin/Lef1 signalling in postnatal keratinocytes, we conclude that the level of β-catenin signalling determines whether keratinocytes differentiate into hair or Interfollicular Epidermis, and that perturbation of the pathway by overexpression of ΔNLef1 can lead to skin tumour formation.
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Expression of ΔNLef1 in mouse Epidermis results in differentiation of hair follicles into squamous epidermal cysts and formation of skin tumours
Development (Cambridge England), 2002Co-Authors: Catherin Niemann, David M. Owens, Jorg Hulsken, Walter Birchmeier, Fiona M WattAbstract:To examine the consequences of repressing beta-catenin/Lef1 signalling in mouse Epidermis, we expressed a DeltaNLef1 transgene, which lacks the beta-catenin binding site, under the control of the keratin 14 promoter. No skin abnormalities were detected before the first postnatal hair cycle. However, from 6 weeks of age, mice underwent progressive hair loss which correlated with the development of dermal cysts. The cysts were derived from the base of the hair follicles and expressed morphological and molecular markers of Interfollicular Epidermis. Adult mice developed spontaneous skin tumours, most of which exhibited sebaceous differentiation, which could be indicative of an origin in the upper part of the hair follicle. The transgene continued to be expressed in the tumours and beta-catenin signalling was still inhibited, as evidenced by absence of cyclin D1 expression. However, patched mRNA expression was upregulated, suggesting that the sonic hedgehog pathway might play a role in tumour formation. Based on our results and previous data on the consequences of activating beta-catenin/Lef1 signalling in postnatal keratinocytes, we conclude that the level of beta-catenin signalling determines whether keratinocytes differentiate into hair or Interfollicular Epidermis, and that perturbation of the pathway by overexpression of DeltaNLef1 can lead to skin tumour formation.