The Experts below are selected from a list of 9516 Experts worldwide ranked by ideXlab platform
Fiona M Watt - One of the best experts on this subject based on the ideXlab platform.
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human Epidermal Stem Cell differentiation is modulated by specific lipid subspecies
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Matteo Vietri Rudan, A K Mishra, Christian Klose, Ulrike S Eggert, Fiona M WattAbstract:While the lipids of the outer layers of mammalian epidermis and their contribution to barrier formation have been extensively described, the role of individual lipid species in the onset of keratinocyte differentiation remains unknown. A lipidomic analysis of primary human keratinocytes revealed accumulation of numerous lipid species during suspension-induced differentiation. A small interfering RNA screen of 258 lipid-modifying enzymes identified two genes that on knockdown induced Epidermal differentiation: ELOVL1, encoding elongation of very long-chain fatty acids protein 1, and SLC27A1, encoding fatty acid transport protein 1. By intersecting lipidomic datasets from suspension-induced differentiation and knockdown keratinocytes, we pinpointed candidate bioactive lipid subspecies as differentiation regulators. Several of these-ceramides and glucosylceramides-induced differentiation when added to primary keratinocytes in culture. Our results reveal the potential of lipid subspecies to regulate exit from the Epidermal Stem Cell compartment.
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patterning of human Epidermal Stem Cells on undulating elastomer substrates reflects differences in Cell stiffness
Acta Biomaterialia, 2019Co-Authors: Seyedeh Atefeh Mobasseri, Sebastiaan Zijl, Vasiliki Salameti, Gernot Walko, Andrew Stannard, Sergi Garciamanyes, Fiona M WattAbstract:Abstract In human skin the junction between epidermis and dermis undulates, the width and depth of the undulations varying with age and disease. When primary human Epidermal keratinocytes are seeded on collagen-coated polydimethylsiloxane (PDMS) elastomer substrates that mimic the Epidermal-dermal interface, the Stem Cells become patterned by 24 h, resembling their organisation in living skin. We found that Cell density and nuclear height were higher at the base than the tips of the PDMS features. Cells on the tips not only expressed higher levels of the Stem Cell marker β1 integrin but also had elevated E-cadherin, Desmoglein 3 and F-actin than Cells at the base. In contrast, levels of the transcriptional cofactor MAL were higher at the base. AFM measurements established that the Young’s modulus of Cells on the tips was lower than on the base or Cells on flat substrates. The differences in Cell stiffness were dependent on Rho kinase activity and interCellular adhesion. On flat substrates the Young’s modulus of calcium-dependent interCellular junctions was higher than that of the Cell body, again dependent on Rho kinase. Cell patterning was influenced by the angle of the slope on undulating substrates. Our observations are consistent with the concept that Epidermal Stem Cell patterning is dependent on mechanical forces exerted at interCellular junctions in response to undulations in the Epidermal-dermal interface. Statement of significance In human skin the Epidermal-dermal junction undulates and Epidermal Stem Cells are patterned according to their position. We previously created collagen-coated polydimethylsiloxane (PDMS) elastomer substrates that mimic the undulations and provide sufficient topographical information for Stem Cells to cluster on the tips. Here we show that the stiffness of Cells on the tips is lower than Cells on the base. The differences in Cell stiffness depend on Rho kinase activity and interCellular adhesion. We propose that Epidermal Stem Cell patterning is determined by mechanical forces exerted at interCellular junctions in response to the slope of the undulations.
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engineered microenvironments to direct Epidermal Stem Cell behavior at single Cell resolution
Developmental Cell, 2016Co-Authors: Fiona M WattAbstract:Mammalian epidermis is maintained through proliferation of Stem Cells and differentiation of their progeny. The balance between self-renewal and differentiation is controlled by a variety of interacting intrinsic and extrinsic factors. Although the nature of these interactions is complex, they can be modeled in a reductionist fashion by capturing single Epidermal Stem Cells on micropatterned substrates and exposing them to individual stimuli, alone or in combination, over defined time points. These studies have shown that different extrinsic stimuli trigger a common outcome—initiation of terminal differentiation—by activating different signaling pathways and eliciting different transcriptional responses.
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mammalian skin Cell biology at the interface between laboratory and clinic
Science, 2014Co-Authors: Fiona M WattAbstract:Mammalian skin research represents the convergence of three complementary disciplines: Cell biology, mouse genetics, and dermatology. The skin provides a paradigm for current research in Cell adhesion, inflammation, and tissue Stem Cells. Here, I discuss recent insights into the Cell biology of skin. Single-Cell analysis has revealed that human Epidermal Stem Cells are heterogeneous and differentiate in response to multiple extrinsic signals. Live-Cell imaging, optogenetics, and Cell ablation experiments show skin Cells to be remarkably dynamic. High-throughput, genome-wide approaches have yielded unprecedented insights into the circuitry that controls Epidermal Stem Cell fate. Last, integrative biological analysis of human skin disorders has revealed unexpected functions for elements of the skin that were previously considered purely structural.
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Markers of Epidermal Stem Cell Subpopulations in Adult Mammalian Skin
Cold Spring Harbor perspectives in medicine, 2014Co-Authors: Kai Kretzschmar, Fiona M WattAbstract:The epidermis is the outermost layer of mammalian skin and comprises a multilayered epithelium, the interfollicular epidermis, with associated hair follicles, sebaceous glands, and eccrine sweat glands. As in other epithelia, adult Stem Cells within the epidermis maintain tissue homeostasis and contribute to repair of tissue damage. The bulge of hair follicles, where DNA-label-retaining Cells reside, was traditionally regarded as the sole Epidermal Stem Cell compartment. However, in recent years multiple Stem Cell populations have been identified. In this review, we discuss the different Stem Cell compartments of adult murine and human epidermis, the markers that they express, and the assays that are used to characterize Epidermal Stem Cell properties.
Maria A. Blasco - One of the best experts on this subject based on the ideXlab platform.
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a p53 dependent response limits Epidermal Stem Cell functionality and organismal size in mice with short telomeres
PLOS ONE, 2009Co-Authors: Ignacio Flores, Maria A. BlascoAbstract:Telomere maintenance is essential to ensure proper size and function of organs with a high turnover. In particular, a dwarf phenotype as well as phenotypes associated to premature loss of tissue regeneration, including the skin (hair loss, hair graying, decreased wound healing), are found in mice deficient for telomerase, the enzyme responsible for maintaining telomere length. Coincidental with the appearance of these phenotypes, p53 is found activated in several tissues from these mice, where is thought to trigger Cellular senescence and/or apoptotic responses. Here, we show that p53 abrogation rescues both the small size phenotype and restitutes the functionality of Epidermal Stem Cells (ESC) of telomerase-deficient mice with dysfunctional telomeres. In particular, p53 ablation restores hair growth, skin renewal and wound healing responses upon mitogenic induction, as well as rescues ESCmobilization defects in vivo and defective ESC clonogenic activity in vitro. This recovery of ESC functions is accompanied by a downregulation of senescence markers and an increased proliferation in the skin and kidney of telomerase-deficient mice with critically short telomeres without changes in apoptosis rates. Together, these findings indicate the existence of a p53-dependent senescence response acting on Stem/progenitor Cells with dysfunctional telomeres that is actively limiting their contribution to tissue regeneration, thereby impinging on tissue fitness.
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telomerase reverses Epidermal hair follicle Stem Cell defects and loss of long term survival associated with critically short telomeres
Journal of Cell Biology, 2007Co-Authors: Irene Sieglcachedenier, Ignacio Flores, Peter Klatt, Maria A. BlascoAbstract:Organ homeostasis and organismal survival are related to the ability of Stem Cells to sustain tissue regeneration. As a consequence of accelerated telomerase shortening, telomerase-deficient mice show defective tissue regeneration and premature death. This suggests a direct impact of telomere length and telomerase activity on Stem Cell biology. We recently found that short telomeres impair the ability of Epidermal Stem Cells to mobilize out of the hair follicle (HF) niche, resulting in impaired skin and hair growth and in the suppression of Epidermal Stem Cell proliferative capacity in vitro. Here, we demonstrate that telomerase reintroduction in mice with critically short telomeres is sufficient to correct Epidermal HF Stem Cell defects. Additionally, telomerase reintroduction into these mice results in a normal life span by preventing degenerative pathologies in the absence of increased tumorigenesis.
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effects of telomerase and telomere length on Epidermal Stem Cell behavior
Science, 2005Co-Authors: Ignacio Flores, Maria L Cayuela, Maria A. BlascoAbstract:A key process in organ homeostasis is the mobilization of Stem Cells out of their niches. We show through analysis of mouse models that telomere length, as well as the catalytic component of telomerase, Tert, are critical determinants in the mobilization of Epidermal Stem Cells. Telomere shortening inhibited mobilization of Stem Cells out of their niche, impaired hair growth, and resulted in suppression of Stem Cell proliferative capacity in vitro. In contrast, Tert overexpression in the absence of changes in telomere length promoted Stem Cell mobilization, hair growth, and Stem Cell proliferation in vitro. The effects of telomeres and telomerase on Stem Cell biology anticipate their role in cancer and aging.
Nicolas Grasset - One of the best experts on this subject based on the ideXlab platform.
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a single Epidermal Stem Cell strategy for safe ex vivo gene therapy
Embo Molecular Medicine, 2015Co-Authors: Stephanie Lathion, Ariane Rochat, Graham Knott, Alessandra Recchia, Danielle Martinet, Sara Benmohammed, Nicolas GrassetAbstract:There is a widespread agreement from patient and professional organisations alike that the safety of Stem Cell therapeutics is of paramount importance, particularly for ex vivo autologous gene therapy. Yet current technology makes it difficult to thoroughly evaluate the behaviour of genetically corrected Stem Cells before they are transplanted. To address this, we have developed a strategy that permits transplantation of a clonal population of genetically corrected autologous Stem Cells that meet stringent selection criteria and the principle of precaution. As a proof of concept, we have stably transduced Epidermal Stem Cells (holoclones) obtained from a patient suffering from recessive dystrophic epidermolysis bullosa. Holoclones were infected with self-inactivating retroviruses bearing a COL7A1 cDNA and cloned before the progeny of individual Stem Cells were characterised using a number of criteria. Clonal analysis revealed a great deal of heterogeneity among transduced Stem Cells in their capacity to produce functional type VII collagen (COLVII). Selected transduced Stem Cells transplanted onto immunodeficient mice regenerated a non-blistering epidermis for months and produced a functional COLVII. Safety was assessed by determining the sites of proviral integration, rearrangements and hit genes and by whole-genome sequencing. The progeny of the selected Stem Cells also had a diploid karyotype, was not tumorigenic and did not disseminate after long-term transplantation onto immunodeficient mice. In conclusion, a clonal strategy is a powerful and efficient means of by-passing the heterogeneity of a transduced Stem Cell population. It guarantees a safe and homogenous medicinal product, fulfilling the principle of precaution and the requirements of regulatory affairs. Furthermore, a clonal strategy makes it possible to envision exciting gene-editing technologies like zinc finger nucleases, TALENs and homologous recombination for next-generation gene therapy.
Salvador Aznar Benitah - One of the best experts on this subject based on the ideXlab platform.
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Human Epidermal Stem Cell Function Is Regulated by Circadian Oscillations
Cell stem cell, 2013Co-Authors: Peggy Janich, Guiomar Solanas, Nuno Miguel Luis, Kiana Toufighi, Susann Minkwitz, Luis Serrano, Ben Lehner, Salvador Aznar BenitahAbstract:Human skin copes with harmful environmental factors that are circadian in nature, yet how circadian rhythms modulate the function of human Epidermal Stem Cells is mostly unknown. Here we show that in human Epidermal Stem Cells and their differentiated counterparts, core clock genes peak in a successive and phased manner, establishing distinct temporal intervals during the 24 hr day period. Each of these successive clock waves is associated with a peak in the expression of subsets of transcripts that temporally segregate the predisposition of Epidermal Stem Cells to respond to cues that regulate their proliferation or differentiation, such as TGFβ and calcium. Accordingly, circadian arrhythmia profoundly affects Stem Cell function in culture and in vivo. We hypothesize that this intricate mechanism ensures homeostasis by providing Epidermal Stem Cells with environmentally relevant temporal functional cues during the course of the day and that its perturbation may contribute to aging and carcinogenesis.
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Defining an Epidermal Stem Cell epigenetic network
Nature Cell Biology, 2012Co-Authors: Salvador Aznar BenitahAbstract:Dynamic changes in the chromatin of adult Stem Cells are required to establish the gene expression profiles associated with Stem Cell self-renewal and differentiation. A complex genetic network of chromatin remodellers and epigenetic factors orchestrate these genome-wide changes in human Epidermal Stem Cells.
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the circadian molecular clock creates Epidermal Stem Cell heterogeneity
Nature, 2011Co-Authors: Peggy Janich, Gloria Pascual, Anna Merlossuarez, Eduard Batlle, Jurgen A Ripperger, Urs Albrecht, Haiying M Cheng, Karl Obrietan, Luciano Di Croce, Salvador Aznar BenitahAbstract:Murine Epidermal Stem Cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of Stem Cells becomes active during each round of morphogenesis, indicating that Stem Cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle Stem Cell niche contains coexisting populations of Cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of Stem Cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant Stem Cells, respectively. Stem Cell arrhythmia also led to premature Epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of Epidermal Stem Cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.
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jarid2 regulates mouse Epidermal Stem Cell activation and differentiation
The EMBO Journal, 2011Co-Authors: Stefania Mejetta, Lluis Morey, Gloria Pascual, Bernd Kuebler, Luciano Di Croce, Matthew R Mysliwiec, Youngsook Lee, Ramin Shiekhattar, Salvador Aznar BenitahAbstract:Jarid2 is required for the genomic recruitment of the polycomb repressive complex-2 (PRC2) in embryonic Stem Cells. However, its specific role during late development and adult tissues remains largely uncharacterized. Here, we show that deletion of Jarid2 in mouse epidermis reduces the proliferation and potentiates the differentiation of postnatal Epidermal progenitors, without affecting Epidermal development. In neonatal epidermis, Jarid2 deficiency reduces H3K27 trimethylation, a chromatin repressive mark, in Epidermal differentiation genes previously shown to be targets of the PRC2. However, in adult epidermis Jarid2 depletion does not affect interfollicular Epidermal differentiation but results in delayed hair follicle (HF) cycling as a consequence of decreased proliferation of HF Stem Cells and their progeny. We conclude that Jarid2 is required for the scheduled proliferation of Epidermal Stem and progenitor Cells necessary to maintain Epidermal homeostasis.
Ignacio Flores - One of the best experts on this subject based on the ideXlab platform.
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a p53 dependent response limits Epidermal Stem Cell functionality and organismal size in mice with short telomeres
PLOS ONE, 2009Co-Authors: Ignacio Flores, Maria A. BlascoAbstract:Telomere maintenance is essential to ensure proper size and function of organs with a high turnover. In particular, a dwarf phenotype as well as phenotypes associated to premature loss of tissue regeneration, including the skin (hair loss, hair graying, decreased wound healing), are found in mice deficient for telomerase, the enzyme responsible for maintaining telomere length. Coincidental with the appearance of these phenotypes, p53 is found activated in several tissues from these mice, where is thought to trigger Cellular senescence and/or apoptotic responses. Here, we show that p53 abrogation rescues both the small size phenotype and restitutes the functionality of Epidermal Stem Cells (ESC) of telomerase-deficient mice with dysfunctional telomeres. In particular, p53 ablation restores hair growth, skin renewal and wound healing responses upon mitogenic induction, as well as rescues ESCmobilization defects in vivo and defective ESC clonogenic activity in vitro. This recovery of ESC functions is accompanied by a downregulation of senescence markers and an increased proliferation in the skin and kidney of telomerase-deficient mice with critically short telomeres without changes in apoptosis rates. Together, these findings indicate the existence of a p53-dependent senescence response acting on Stem/progenitor Cells with dysfunctional telomeres that is actively limiting their contribution to tissue regeneration, thereby impinging on tissue fitness.
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telomerase reverses Epidermal hair follicle Stem Cell defects and loss of long term survival associated with critically short telomeres
Journal of Cell Biology, 2007Co-Authors: Irene Sieglcachedenier, Ignacio Flores, Peter Klatt, Maria A. BlascoAbstract:Organ homeostasis and organismal survival are related to the ability of Stem Cells to sustain tissue regeneration. As a consequence of accelerated telomerase shortening, telomerase-deficient mice show defective tissue regeneration and premature death. This suggests a direct impact of telomere length and telomerase activity on Stem Cell biology. We recently found that short telomeres impair the ability of Epidermal Stem Cells to mobilize out of the hair follicle (HF) niche, resulting in impaired skin and hair growth and in the suppression of Epidermal Stem Cell proliferative capacity in vitro. Here, we demonstrate that telomerase reintroduction in mice with critically short telomeres is sufficient to correct Epidermal HF Stem Cell defects. Additionally, telomerase reintroduction into these mice results in a normal life span by preventing degenerative pathologies in the absence of increased tumorigenesis.
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effects of telomerase and telomere length on Epidermal Stem Cell behavior
Science, 2005Co-Authors: Ignacio Flores, Maria L Cayuela, Maria A. BlascoAbstract:A key process in organ homeostasis is the mobilization of Stem Cells out of their niches. We show through analysis of mouse models that telomere length, as well as the catalytic component of telomerase, Tert, are critical determinants in the mobilization of Epidermal Stem Cells. Telomere shortening inhibited mobilization of Stem Cells out of their niche, impaired hair growth, and resulted in suppression of Stem Cell proliferative capacity in vitro. In contrast, Tert overexpression in the absence of changes in telomere length promoted Stem Cell mobilization, hair growth, and Stem Cell proliferation in vitro. The effects of telomeres and telomerase on Stem Cell biology anticipate their role in cancer and aging.