Valerie Horsley | Yale University (original) (raw)
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Papers by Valerie Horsley
PloS one, 2015
In recent years, several studies have shed light into the processes that regulate epidermal speci... more In recent years, several studies have shed light into the processes that regulate epidermal specification and homeostasis. We previously showed that a broad-spectrum γ-secretase inhibitor DAPT promoted early keratinocyte specification in human embryonic stem cells triggered to undergo ectoderm specification. Here, we show that DAPT accelerates human embryonic stem cell differentiation and induces expression of the ectoderm protein AP2. Furthermore, we utilize RNA sequencing to identify several candidate regulators of ectoderm specification including those involved in epithelial and epidermal development in human embryonic stem cells. Genes associated with transcriptional regulation and growth factor activity are significantly enriched upon DAPT treatment during specification of human embryonic stem cells to the ectoderm lineage. The human ectoderm cell signature identified in this study contains several genes expressed in ectodermal and epithelial tissues. Importantly, these genes a...
Wiley interdisciplinary reviews. Developmental biology
Stratified squamous epithelial cells are found in a number of organs, including the skin epidermi... more Stratified squamous epithelial cells are found in a number of organs, including the skin epidermis and the thymus. The progenitor cells of the developing epidermis form a multi-layered epithelium and appendages, like the hair follicle, to generate an essential barrier to protect against water loss and invasion of foreign pathogens. In contrast, the thymic epithelium forms a three-dimensional mesh of keratinocytes that are essential for positive and negative selection of self-restricted T cells. While these distinct stratified epithelial tissues derive from distinct embryonic germ layers, both tissues instruct immunity, and the epithelial differentiation programs and molecular mechanisms that control their development are remarkably similar. In this review, we aim to highlight some of the similarities between the thymus and the skin epidermis and its appendages during developmental specification.
Proceedings of the National Academy of Sciences of the United States of America, Jan 15, 2014
Understanding the epigenetic mechanisms that control the activation of adult stem cells holds the... more Understanding the epigenetic mechanisms that control the activation of adult stem cells holds the promise of tissue and organ regeneration. Hair follicle stem cells have emerged as a prime model to study stem cell activation. Wnt/β-catenin signaling controls multiple aspects of skin epithelial regeneration, with its excessive activity promoting the hyperactivation of hair follicle stem/progenitor cells and tumorigenesis. The contribution of chromatin factors in regulating Wnt/β-catenin pathway function in these processes is unknown. Here, we show that chromatin effector Pygopus homolog 2 (Pygo2) produced by the epithelial cells facilitates depilation-induced hair regeneration, as well as β-catenin-induced activation of hair follicle stem/early progenitor cells and trichofolliculoma-like skin hyperplasia. Pygo2 maximizes the expression of Wnt/β-catenin targets, but is dispensable for β-catenin-mediated expansion of LIM/homeobox protein Lhx2(+) cells, in the stem/early progenitor cell...
Adipocyte, 2014
The study of adipose tissue in vivo has been significantly advanced through the use of genetic mo... more The study of adipose tissue in vivo has been significantly advanced through the use of genetic mouse models. While the aP2-cre BI and aP2-cre Salk lines have been widely used to target adipose tissue, the specificity of these lines for adipocytes has recently been questioned. here we characterize cre recombinase activity in multiple cell populations of the major adipose tissue depots of these and other cre lines using the membrane-Tomato/membrane-GFP (mT/mG) dual fluorescent reporter. We find that the aP2-cre BI and aP2-cre Salk lines lack specificity for adipocytes within adipose tissue, and that the aP2-cre BI line does not efficiently target adipocytes in white adipose depots. Alternatively, the Adiponectin-creeRT line shows high efficiency and specificity for adipocytes, while the PdgfRα-creeRUcL and PdgfRα-creeRJhU lines do not efficiently target adipocyte precursor cells in the major adipose depots. Instead, we show that the PdgfRα-cre line is preferable for studies targeting adipocyte precursor cells in vivo.
Proceedings of the National Academy of Sciences, 2013
Physical Review Letters, 2012
To understand how the mechanical properties of tissues emerge from interactions of multiple cells... more To understand how the mechanical properties of tissues emerge from interactions of multiple cells, we measure traction stresses of cohesive colonies of 1-27 cells adherent to soft substrates. We find that traction stresses are generally localized at the periphery of the colony and the total traction force scales with the colony radius. For large colony sizes the scaling appears to approach linear, suggesting the emergence of an apparent surface tension of order 10 −3 N/m. A simple model of the cell colony as a contractile elastic medium coupled to the substrate captures the spatial distribution of traction forces and the scaling of traction forces with the colony size.
Nature Cell Biology, 2011
Over the past decade, it has become increasingly clear that many tissues have regenerative capabi... more Over the past decade, it has become increasingly clear that many tissues have regenerative capabilities. The challenge has been to find the stem cells or progenitors that are responsible for tissue renewal and repair. The revolution in technological advances that permit sophisticated spatial, temporal and kinetic analyses of stem cells has allowed stem cell hunters to ferret out where stem cells live, and to monitor when they come and go from these hiding places.
Microscopy and Microanalysis, 2008
Extended abstract of a paper presented at Microscopy and Microanalysis 2008 in Albuquerque, New M... more Extended abstract of a paper presented at Microscopy and Microanalysis 2008 in Albuquerque, New Mexico, USA, August 3 – August 7, 2008
Journal of Investigative Dermatology, 2013
Skin wound repair requires complex and highly coordinated interactions between keratinocytes, fib... more Skin wound repair requires complex and highly coordinated interactions between keratinocytes, fibroblasts, and immune cells to restore the epidermal barrier and tissue architecture after acute injury. The cytokine IL-22 mediates unidirectional signaling from immune cells to epithelial cells during injury of peripheral tissues such as the liver and colon, where IL-22 causes epithelial cells to produce antibacterial proteins, express mucins, and enhance epithelial regeneration. In this study, we used IL-22 À / À mice to investigate the in vivo role for IL-22 in acute skin wounding. We found that IL-22 À / À mice displayed major defects in the skin's dermal compartment after full-thickness wounding. We also found that IL-22 signaling is active in fibroblasts, using in vitro assays with primary fibroblasts, and that IL-22 directs extracellular matrix (ECM) gene expression and myofibroblast differentiation both in vitro and in vivo. These data define roles of IL-22 beyond epithelial cross talk, and suggest that IL-22 has a previously unidentified role in skin repair by mediating interactions between immune cells and fibroblasts.
Journal of Experimental Medicine, 2009
Genes & Development, 2014
Genes & Development, 2008
Cellular and Molecular Life Sciences, 2012
The epidermis and its appendages, such as the hair follicle (HF), continually regenerate througho... more The epidermis and its appendages, such as the hair follicle (HF), continually regenerate throughout postnatal mammalian life due to the activity of resident epithelial stem cells (SCs). The follicular SC niche, or the bulge, is composed of a heterogeneous population of self-renewing multipotent cells. Multiple intrinsic molecular mechanisms promote the transition of follicular SCs from quiescence to activation. In addition, numerous extrinsic cell types influence the activity and characteristics of bulge cells. Ultimately, the balance between these intrinsic and extrinsic mechanisms influences the function of bulge cells during homeostasis and tissue regeneration and likely contributes to skin tumorigenesis. Here, we review both the intrinsic and extrinsic factors that contribute to the skin SC niche.
PloS one, 2015
In recent years, several studies have shed light into the processes that regulate epidermal speci... more In recent years, several studies have shed light into the processes that regulate epidermal specification and homeostasis. We previously showed that a broad-spectrum γ-secretase inhibitor DAPT promoted early keratinocyte specification in human embryonic stem cells triggered to undergo ectoderm specification. Here, we show that DAPT accelerates human embryonic stem cell differentiation and induces expression of the ectoderm protein AP2. Furthermore, we utilize RNA sequencing to identify several candidate regulators of ectoderm specification including those involved in epithelial and epidermal development in human embryonic stem cells. Genes associated with transcriptional regulation and growth factor activity are significantly enriched upon DAPT treatment during specification of human embryonic stem cells to the ectoderm lineage. The human ectoderm cell signature identified in this study contains several genes expressed in ectodermal and epithelial tissues. Importantly, these genes a...
Wiley interdisciplinary reviews. Developmental biology
Stratified squamous epithelial cells are found in a number of organs, including the skin epidermi... more Stratified squamous epithelial cells are found in a number of organs, including the skin epidermis and the thymus. The progenitor cells of the developing epidermis form a multi-layered epithelium and appendages, like the hair follicle, to generate an essential barrier to protect against water loss and invasion of foreign pathogens. In contrast, the thymic epithelium forms a three-dimensional mesh of keratinocytes that are essential for positive and negative selection of self-restricted T cells. While these distinct stratified epithelial tissues derive from distinct embryonic germ layers, both tissues instruct immunity, and the epithelial differentiation programs and molecular mechanisms that control their development are remarkably similar. In this review, we aim to highlight some of the similarities between the thymus and the skin epidermis and its appendages during developmental specification.
Proceedings of the National Academy of Sciences of the United States of America, Jan 15, 2014
Understanding the epigenetic mechanisms that control the activation of adult stem cells holds the... more Understanding the epigenetic mechanisms that control the activation of adult stem cells holds the promise of tissue and organ regeneration. Hair follicle stem cells have emerged as a prime model to study stem cell activation. Wnt/β-catenin signaling controls multiple aspects of skin epithelial regeneration, with its excessive activity promoting the hyperactivation of hair follicle stem/progenitor cells and tumorigenesis. The contribution of chromatin factors in regulating Wnt/β-catenin pathway function in these processes is unknown. Here, we show that chromatin effector Pygopus homolog 2 (Pygo2) produced by the epithelial cells facilitates depilation-induced hair regeneration, as well as β-catenin-induced activation of hair follicle stem/early progenitor cells and trichofolliculoma-like skin hyperplasia. Pygo2 maximizes the expression of Wnt/β-catenin targets, but is dispensable for β-catenin-mediated expansion of LIM/homeobox protein Lhx2(+) cells, in the stem/early progenitor cell...
Adipocyte, 2014
The study of adipose tissue in vivo has been significantly advanced through the use of genetic mo... more The study of adipose tissue in vivo has been significantly advanced through the use of genetic mouse models. While the aP2-cre BI and aP2-cre Salk lines have been widely used to target adipose tissue, the specificity of these lines for adipocytes has recently been questioned. here we characterize cre recombinase activity in multiple cell populations of the major adipose tissue depots of these and other cre lines using the membrane-Tomato/membrane-GFP (mT/mG) dual fluorescent reporter. We find that the aP2-cre BI and aP2-cre Salk lines lack specificity for adipocytes within adipose tissue, and that the aP2-cre BI line does not efficiently target adipocytes in white adipose depots. Alternatively, the Adiponectin-creeRT line shows high efficiency and specificity for adipocytes, while the PdgfRα-creeRUcL and PdgfRα-creeRJhU lines do not efficiently target adipocyte precursor cells in the major adipose depots. Instead, we show that the PdgfRα-cre line is preferable for studies targeting adipocyte precursor cells in vivo.
Proceedings of the National Academy of Sciences, 2013
Physical Review Letters, 2012
To understand how the mechanical properties of tissues emerge from interactions of multiple cells... more To understand how the mechanical properties of tissues emerge from interactions of multiple cells, we measure traction stresses of cohesive colonies of 1-27 cells adherent to soft substrates. We find that traction stresses are generally localized at the periphery of the colony and the total traction force scales with the colony radius. For large colony sizes the scaling appears to approach linear, suggesting the emergence of an apparent surface tension of order 10 −3 N/m. A simple model of the cell colony as a contractile elastic medium coupled to the substrate captures the spatial distribution of traction forces and the scaling of traction forces with the colony size.
Nature Cell Biology, 2011
Over the past decade, it has become increasingly clear that many tissues have regenerative capabi... more Over the past decade, it has become increasingly clear that many tissues have regenerative capabilities. The challenge has been to find the stem cells or progenitors that are responsible for tissue renewal and repair. The revolution in technological advances that permit sophisticated spatial, temporal and kinetic analyses of stem cells has allowed stem cell hunters to ferret out where stem cells live, and to monitor when they come and go from these hiding places.
Microscopy and Microanalysis, 2008
Extended abstract of a paper presented at Microscopy and Microanalysis 2008 in Albuquerque, New M... more Extended abstract of a paper presented at Microscopy and Microanalysis 2008 in Albuquerque, New Mexico, USA, August 3 – August 7, 2008
Journal of Investigative Dermatology, 2013
Skin wound repair requires complex and highly coordinated interactions between keratinocytes, fib... more Skin wound repair requires complex and highly coordinated interactions between keratinocytes, fibroblasts, and immune cells to restore the epidermal barrier and tissue architecture after acute injury. The cytokine IL-22 mediates unidirectional signaling from immune cells to epithelial cells during injury of peripheral tissues such as the liver and colon, where IL-22 causes epithelial cells to produce antibacterial proteins, express mucins, and enhance epithelial regeneration. In this study, we used IL-22 À / À mice to investigate the in vivo role for IL-22 in acute skin wounding. We found that IL-22 À / À mice displayed major defects in the skin's dermal compartment after full-thickness wounding. We also found that IL-22 signaling is active in fibroblasts, using in vitro assays with primary fibroblasts, and that IL-22 directs extracellular matrix (ECM) gene expression and myofibroblast differentiation both in vitro and in vivo. These data define roles of IL-22 beyond epithelial cross talk, and suggest that IL-22 has a previously unidentified role in skin repair by mediating interactions between immune cells and fibroblasts.
Journal of Experimental Medicine, 2009
Genes & Development, 2014
Genes & Development, 2008
Cellular and Molecular Life Sciences, 2012
The epidermis and its appendages, such as the hair follicle (HF), continually regenerate througho... more The epidermis and its appendages, such as the hair follicle (HF), continually regenerate throughout postnatal mammalian life due to the activity of resident epithelial stem cells (SCs). The follicular SC niche, or the bulge, is composed of a heterogeneous population of self-renewing multipotent cells. Multiple intrinsic molecular mechanisms promote the transition of follicular SCs from quiescence to activation. In addition, numerous extrinsic cell types influence the activity and characteristics of bulge cells. Ultimately, the balance between these intrinsic and extrinsic mechanisms influences the function of bulge cells during homeostasis and tissue regeneration and likely contributes to skin tumorigenesis. Here, we review both the intrinsic and extrinsic factors that contribute to the skin SC niche.