Publications by authors named "Sarah E Millar"

66 Publications

Author Correction: MiR-31 promotes mammary stem cell expansion and breast tumorigenesis by suppressing Wnt signaling antagonists.

Nat Commun 2020 Oct 15;11(1):5308. Epub 2020 Oct 15.

State Key Laboratories for Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-19103-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567098PMC
October 2020

FAM20B-catalyzed glycosaminoglycans control murine tooth number by restricting FGFR2b signaling.

BMC Biol 2020 07 14;18(1):87. Epub 2020 Jul 14.

Department of Biomedical Sciences, Texas A&M University College of Dentistry, 3302 Gaston Ave, Dallas, TX, 75246, USA.

Background: The formation of supernumerary teeth is an excellent model for studying the molecular mechanisms that control stem/progenitor cell homeostasis needed to generate a renewable source of replacement cells and tissues. Although multiple growth factors and transcriptional factors have been associated with supernumerary tooth formation, the regulatory inputs of extracellular matrix in this regenerative process remains poorly understood.

Results: In this study, we present evidence that disrupting glycosaminoglycans (GAGs) in the dental epithelium of mice by inactivating FAM20B, a xylose kinase essential for GAG assembly, leads to supernumerary tooth formation in a pattern reminiscent of replacement teeth. The dental epithelial GAGs confine murine tooth number by restricting the homeostasis of Sox2(+) dental epithelial stem/progenitor cells in a non-autonomous manner. FAM20B-catalyzed GAGs regulate the cell fate of dental lamina by restricting FGFR2b signaling at the initial stage of tooth development to maintain a subtle balance between the renewal and differentiation of Sox2(+) cells. At the later cap stage, WNT signaling functions as a relay cue to facilitate the supernumerary tooth formation.

Conclusions: The novel mechanism we have characterized through which GAGs control the tooth number in mice may also be more broadly relevant for potentiating signaling interactions in other tissues during development and tissue homeostasis.
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http://dx.doi.org/10.1186/s12915-020-00813-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359594PMC
July 2020

Identifying Treatments for Taste and Smell Disorders: Gaps and Opportunities.

Chem Senses 2020 10;45(7):493-502

Monell Chemical Senses Center, Philadelphia, PA, USA.

The chemical senses of taste and smell play a vital role in conveying information about ourselves and our environment. Tastes and smells can warn against danger and also contribute to the daily enjoyment of food, friends and family, and our surroundings. Over 12% of the US population is estimated to experience taste and smell (chemosensory) dysfunction. Yet, despite this high prevalence, long-term, effective treatments for these disorders have been largely elusive. Clinical successes in other sensory systems, including hearing and vision, have led to new hope for developments in the treatment of chemosensory disorders. To accelerate cures, we convened the "Identifying Treatments for Taste and Smell Disorders" conference, bringing together basic and translational sensory scientists, health care professionals, and patients to identify gaps in our current understanding of chemosensory dysfunction and next steps in a broad-based research strategy. Their suggestions for high-yield next steps were focused in 3 areas: increasing awareness and research capacity (e.g., patient advocacy), developing and enhancing clinical measures of taste and smell, and supporting new avenues of research into cellular and therapeutic approaches (e.g., developing human chemosensory cell lines, stem cells, and gene therapy approaches). These long-term strategies led to specific suggestions for immediate research priorities that focus on expanding our understanding of specific responses of chemosensory cells and developing valuable assays to identify and document cell development, regeneration, and function. Addressing these high-priority areas should accelerate the development of novel and effective treatments for taste and smell disorders.
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http://dx.doi.org/10.1093/chemse/bjaa038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545248PMC
October 2020

How a Bird Gets Its Feathers: Insights from Chromatin Looping.

Dev Cell 2020 06;53(5):493-495

Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

Mechanisms controlling skin heterogeneity are poorly understood. In this issue of Developmental Cell, Liang et al. show that in chicken, the difference in β-keratin genes expressed in feathered and scaly skin is regulated via typical enhancers, while differential expression within individual feathers correlates with chromatin looping within the gene cluster.
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http://dx.doi.org/10.1016/j.devcel.2020.05.008DOI Listing
June 2020

HDAC3 ensures stepwise epidermal stratification via NCoR/SMRT-reliant mechanisms independent of its histone deacetylase activity.

Genes Dev 2020 07 28;34(13-14):973-988. Epub 2020 May 28.

Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Chromatin modifiers play critical roles in epidermal development, but the functions of histone deacetylases in this context are poorly understood. The class I HDAC, HDAC3, is of particular interest because it plays divergent roles in different tissues by partnering with tissue-specific transcription factors. We found that HDAC3 is expressed broadly in embryonic epidermis and is required for its orderly stepwise stratification. HDAC3 protein stability in vivo relies on NCoR and SMRT, which function redundantly in epidermal development. However, point mutations in the NCoR and SMRT deacetylase-activating domains, which are required for HDAC3's enzymatic function, permit normal stratification, indicating that HDAC3's roles in this context are largely independent of its histone deacetylase activity. HDAC3-bound sites are significantly enriched for predicted binding motifs for critical epidermal transcription factors including AP1, GRHL, and KLF family members. Our results suggest that among these, HDAC3 operates in conjunction with KLF4 to repress inappropriate expression of , , and In parallel, HDAC3 suppresses expression of inflammatory cytokines through a -dependent mechanism. These data identify HDAC3 as a hub coordinating multiple aspects of epidermal barrier acquisition.
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http://dx.doi.org/10.1101/gad.333674.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328513PMC
July 2020

Fractionated head and neck irradiation impacts taste progenitors, differentiated taste cells, and Wnt/β-catenin signaling in adult mice.

Sci Rep 2019 11 29;9(1):17934. Epub 2019 Nov 29.

Department of Cell & Developmental Biology, University of Colorado Anschutz Medical Campus, Mail Stop 8108, 12801 East 17th Avenue, Aurora, CO, 80045, USA.

Head and neck cancer patients receiving conventional repeated, low dose radiotherapy (fractionated IR) suffer from taste dysfunction that can persist for months and often years after treatment. To understand the mechanisms underlying functional taste loss, we established a fractionated IR mouse model to characterize how taste buds are affected. Following fractionated IR, we found as in our previous study using single dose IR, taste progenitor proliferation was reduced and progenitor cell number declined, leading to interruption in the supply of new taste receptor cells to taste buds. However, in contrast to a single dose of IR, we did not encounter increased progenitor cell death in response to fractionated IR. Instead, fractionated IR induced death of cells within taste buds. Overall, taste buds were smaller and fewer following fractionated IR, and contained fewer differentiated cells. In response to fractionated IR, expression of Wnt pathway genes, Ctnnb1, Tcf7, Lef1 and Lgr5 were reduced concomitantly with reduced progenitor proliferation. However, recovery of Wnt signaling post-IR lagged behind proliferative recovery. Overall, our data suggest carefully timed, local activation of Wnt/β-catenin signaling may mitigate radiation injury and/or speed recovery of taste cell renewal following fractionated IR.
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http://dx.doi.org/10.1038/s41598-019-54216-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884601PMC
November 2019

A pulpy story.

Authors:
Sarah E Millar

Nat Mater 2019 06;18(6):530-531

Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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http://dx.doi.org/10.1038/s41563-019-0372-xDOI Listing
June 2019

Regional Control of Hairless versus Hair-Bearing Skin by Dkk2.

Cell Rep 2018 12 30;25(11):2981-2991.e3. Epub 2018 Nov 30.

Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Anatomy and Cell Biology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA 19104, USA. Electronic address:

Haired skin is a defining characteristic of mammals. However, some specialized skin regions, such as human palms, soles and ventral wrist, and mouse plantar foot, are entirely hairless. Using mouse plantar skin as a model system, we show that the endogenous secreted Wnt inhibitor DKK2 suppresses plantar hair follicle development and permits the formation of hairless skin. Plantar skin retains all of the mechanistic components needed for hair follicle development, as genetic deletion of Dkk2 permits formation of fully functional plantar hair follicles that give rise to external hair, contain sebaceous glands and a stem cell compartment, and undergo regenerative growth. In the absence of Dkk2, Wnt/β-catenin signaling activity is initially broadly elevated in embryonic plantar skin and gradually becomes patterned, mimicking follicular development in normally haired areas. These data provide a paradigm in which regionally restricted expression of a Wnt inhibitor underlies specification of hairless versus hairy skin.
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http://dx.doi.org/10.1016/j.celrep.2018.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345517PMC
December 2018

Revitalizing Aging Skin through Diet.

Authors:
Sarah E Millar

Cell 2018 11;175(6):1461-1463

Departments of Dermatology and Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Mechanisms underlying aging of the skin dermis are poorly understood. Now, two studies (Marsh et al., 2018; Salzer et al., 2018) describe complementary approaches to this question: Salzer et al. show that aging dermal fibroblasts lose defined identity in a diet-influenced fashion, and Marsh et al. reveal that fibroblast loss over time is compensated by membrane expansion rather than proliferation, resulting in decreased cellular density.
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http://dx.doi.org/10.1016/j.cell.2018.11.016DOI Listing
November 2018

Overexpression of Desmoglein 2 in a Mouse Model of Gorlin Syndrome Enhances Spontaneous Basal Cell Carcinoma Formation through STAT3-Mediated Gli1 Expression.

J Invest Dermatol 2019 02 3;139(2):300-307. Epub 2018 Oct 3.

Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; Sydney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; Leeds Institute of Cancer and Pathology, University of Leeds, UK; School of Molecular and Cellular Biology, University of Leeds, United Kingdom. Electronic address:

Activation of the hedgehog pathway is causative of virtually all sporadic and Gorlin syndrome-related basal cell carcinomas (BCCs), with loss of function of Ptc1 being the most common genomic lesion. Sporadic BCCs also overexpress Dsg2, a desmosomal cadherin normally found in the basal layer. Using a mouse model of Gorlin syndrome (Ptc1 mice), we found that overexpressing Dsg2 in the basal layer (K14-Dsg2/Ptc1 mice) or the superficial epidermis (Inv-Dsg2/Ptc1 mice) resulted in increased spontaneous BCC formation at 3 and 6 months, respectively. The tumors did not show loss of heterozygosity of Ptc1, despite high levels of Gli1 and phosphorylated Stat3. A panel of sporadic human BCCs showed increased staining of both Dsg2 and phosphorylated Stat3 in all nine samples. Overexpression of Dsg2 in ASZ001 cells, a Ptc1 BCC cell line, induced Stat3 phosphorylation and further increased Gli1 levels, in both an autocrine and paracrine manner. Three different Stat3 inhibitors reduced viability and Gli1 expression in ASZ001 cells but not in HaCaT cells. Conversely, stimulation of Stat3 in ASZ001 cells with IL-6 increased Gli1 expression. Our results indicate that Dsg2 enhances canonical hedgehog signaling downstream of Ptc1 to promote BCC development through the activation of phosphorylated Stat3 and regulation of Gli1 expression.
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http://dx.doi.org/10.1016/j.jid.2018.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342634PMC
February 2019

Hox in the Niche Controls Hairy-geneity.

Authors:
Sarah E Millar

Cell Stem Cell 2018 10;23(4):457-458

Departments of Dermatology and Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104, USA. Electronic address:

Patterns of mammalian hair growth vary in different regions of the body, but the mechanisms controlling this heterogeneity are unclear. In this issue of Cell Stem Cell, Yu et al. (2018) show that Hoxc gene expression in hair follicle mesenchyme varies along the anterior-posterior body axis and contributes to regional differences in hair growth.
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http://dx.doi.org/10.1016/j.stem.2018.09.012DOI Listing
October 2018

Meeting report: a hard look at the state of enamel research.

Int J Oral Sci 2017 11 22;9(11):e3. Epub 2017 Nov 22.

Biologic and Materials Sciences and Division of Prosthodontics, University of Michigan, Ann Arbor, USA.

The Encouraging Novel Amelogenesis Models and Ex vivo cell Lines (ENAMEL) Development workshop was held on 23 June 2017 at the Bethesda headquarters of the National Institute of Dental and Craniofacial Research (NIDCR). Discussion topics included model organisms, stem cells/cell lines, and tissues/3D cell culture/organoids. Scientists from a number of disciplines, representing institutions from across the United States, gathered to discuss advances in our understanding of enamel, as well as future directions for the field.
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http://dx.doi.org/10.1038/ijos.2017.40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775332PMC
November 2017

MiR-31 promotes mammary stem cell expansion and breast tumorigenesis by suppressing Wnt signaling antagonists.

Nat Commun 2017 10 19;8(1):1036. Epub 2017 Oct 19.

State Key Laboratories for Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.

MicroRNA-mediated post-transcriptional regulation plays key roles in stem cell self-renewal and tumorigenesis. However, the in vivo functions of specific microRNAs in controlling mammary stem cell (MaSC) activity and breast cancer formation remain poorly understood. Here we show that miR-31 is highly expressed in MaSC-enriched mammary basal cell population and in mammary tumors, and is regulated by NF-κB signaling. We demonstrate that miR-31 promotes mammary epithelial proliferation and MaSC expansion at the expense of differentiation in vivo. Loss of miR-31 compromises mammary tumor growth, reduces the number of cancer stem cells, as well as decreases tumor-initiating ability and metastasis to the lung, supporting its pro-oncogenic function. MiR-31 modulates multiple signaling pathways, including Prlr/Stat5, TGFβ and Wnt/β-catenin. Particularly, it activates Wnt/β-catenin signaling by directly targeting Wnt antagonists, including Dkk1. Importantly, Dkk1 overexpression partially rescues miR31-induced mammary defects. Together, these findings identify miR-31 as the key regulator of MaSC activity and breast tumorigenesis.
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http://dx.doi.org/10.1038/s41467-017-01059-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648844PMC
October 2017

Cytoplasmic chromatin triggers inflammation in senescence and cancer.

Nature 2017 10 4;550(7676):402-406. Epub 2017 Oct 4.

Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence, a form of terminal cell-cycle arrest associated with pro-inflammatory responses. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS-STING (cyclic GMP-AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.
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http://dx.doi.org/10.1038/nature24050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850938PMC
October 2017

NF-κB Participates in Mouse Hair Cycle Control and Plays Distinct Roles in the Various Pelage Hair Follicle Types.

J Invest Dermatol 2018 02 20;138(2):256-264. Epub 2017 Sep 20.

Signal Transduction in Tumor Cells, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. Electronic address:

The transcription factor NF-κB controls key features of hair follicle (HF) development, but the role of NF-κB in adult HF cycle regulation remains obscure. Using NF-κB reporter mouse models, strong NF-κB activity was detected in the secondary hair germ of late telogen and early anagen HFs, suggesting a potential role for NF-κB in HF stem/progenitor cell activation during anagen induction. At mid-anagen, NF-κB activity was observed in the inner root sheath and unilaterally clustered in the HF matrix, which indicates that NF-κB activity is also involved in hair fiber morphogenesis during HF cycling. A mouse model with inducible NF-κB suppression in the epithelium revealed pelage hair-type-dependent functions of NF-κB in cycling HFs. NF-κB participates in telogen-anagen transition in awl and zigzag HFs, and is required for zigzag hair bending and guard HF cycling. Interestingly, zigzag hair shaft bending depends on noncanonical NF-κB signaling, which previously has only been associated with lymphoid cell biology. Furthermore, loss of guard HF cycling suggests that in this particular hair type, NF-κB is indispensable for stem cell activation, maintenance, and/or growth.
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http://dx.doi.org/10.1016/j.jid.2017.08.042DOI Listing
February 2018

β-catenin is required for taste bud cell renewal and behavioral taste perception in adult mice.

PLoS Genet 2017 Aug 28;13(8):e1006990. Epub 2017 Aug 28.

Department of Cell & Developmental Biology and the Rocky Mountain Taste & Smell Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.

Taste stimuli are transduced by taste buds and transmitted to the brain via afferent gustatory fibers. Renewal of taste receptor cells from actively dividing progenitors is finely tuned to maintain taste sensitivity throughout life. We show that conditional β-catenin deletion in mouse taste progenitors leads to rapid depletion of progenitors and Shh+ precursors, which in turn causes taste bud loss, followed by loss of gustatory nerve fibers. In addition, our data suggest LEF1, TCF7 and Wnt3 are involved in a Wnt pathway regulatory feedback loop that controls taste cell renewal in the circumvallate papilla epithelium. Unexpectedly, taste bud decline is greater in the anterior tongue and palate than in the posterior tongue. Mutant mice with this regional pattern of taste bud loss were unable to discern sweet at any concentration, but could distinguish bitter stimuli, albeit with reduced sensitivity. Our findings are consistent with published reports wherein anterior taste buds have higher sweet sensitivity while posterior taste buds are better tuned to bitter, and suggest β-catenin plays a greater role in renewal of anterior versus posterior taste buds.
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http://dx.doi.org/10.1371/journal.pgen.1006990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591015PMC
August 2017

WNT10A mutation causes ectodermal dysplasia by impairing progenitor cell proliferation and KLF4-mediated differentiation.

Nat Commun 2017 06 7;8:15397. Epub 2017 Jun 7.

Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Human WNT10A mutations are associated with developmental tooth abnormalities and adolescent onset of a broad range of ectodermal defects. Here we show that β-catenin pathway activity and adult epithelial progenitor proliferation are reduced in the absence of WNT10A, and identify Wnt-active self-renewing stem cells in affected tissues including hair follicles, sebaceous glands, taste buds, nails and sweat ducts. Human and mouse WNT10A mutant palmoplantar and tongue epithelia also display specific differentiation defects that are mimicked by loss of the transcription factor KLF4. We find that β-catenin interacts directly with region-specific LEF/TCF factors, and with KLF4 in differentiating, but not proliferating, cells to promote expression of specialized keratins required for normal tissue structure and integrity. Our data identify WNT10A as a critical ligand controlling adult epithelial proliferation and region-specific differentiation, and suggest downstream β-catenin pathway activation as a potential approach to ameliorate regenerative defects in WNT10A patients.
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http://dx.doi.org/10.1038/ncomms15397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467248PMC
June 2017

Commensal Microbes and Hair Follicle Morphogenesis Coordinately Drive Treg Migration into Neonatal Skin.

Cell Host Microbe 2017 Apr 23;21(4):467-477.e5. Epub 2017 Mar 23.

Department of Dermatology, University of California, San Francisco, San Francisco, CA, 94143, USA. Electronic address:

Regulatory T cells (Tregs) are required to establish immune tolerance to commensal microbes. Tregs accumulate abruptly in the skin during a defined window of postnatal tissue development. However, the mechanisms mediating Treg migration to neonatal skin are unknown. Here we show that hair follicle (HF) development facilitates the accumulation of Tregs in neonatal skin and that upon skin entry these cells localize to HFs, a primary reservoir for skin commensals. Further, germ-free neonates had reduced skin Tregs indicating that commensal microbes augment Treg accumulation. We identified Ccl20 as a HF-derived, microbiota-dependent chemokine and found its receptor, Ccr6, to be preferentially expressed by Tregs in neonatal skin. The Ccl20-Ccr6 pathway mediated Treg migration in vitro and in vivo. Thus, HF morphogenesis, commensal microbe colonization, and local chemokine production work in concert to recruit Tregs into neonatal skin, thereby establishing this tissue Treg niche early in life.
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http://dx.doi.org/10.1016/j.chom.2017.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516645PMC
April 2017

Regeneration of fat cells from myofibroblasts during wound healing.

Science 2017 02 5;355(6326):748-752. Epub 2017 Jan 5.

Department of Dermatology, Kligman Laboratories, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.

Although regeneration through the reprogramming of one cell lineage to another occurs in fish and amphibians, it has not been observed in mammals. We discovered in the mouse that during wound healing, adipocytes regenerate from myofibroblasts, a cell type thought to be differentiated and nonadipogenic. Myofibroblast reprogramming required neogenic hair follicles, which triggered bone morphogenetic protein (BMP) signaling and then activation of adipocyte transcription factors expressed during development. Overexpression of the BMP antagonist Noggin in hair follicles or deletion of the BMP receptor in myofibroblasts prevented adipocyte formation. Adipocytes formed from human keloid fibroblasts either when treated with BMP or when placed with human hair follicles in vitro Thus, we identify the myofibroblast as a plastic cell type that may be manipulated to treat scars in humans.
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http://dx.doi.org/10.1126/science.aai8792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464786PMC
February 2017

Activation of β-Catenin Signaling in CD133-Positive Dermal Papilla Cells Drives Postnatal Hair Growth.

PLoS One 2016 29;11(7):e0160425. Epub 2016 Jul 29.

Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, Ohio 45267, United States of America.

The hair follicle dermal papilla (DP) contains a unique prominin-1/CD133-positive (CD133+) cell subpopulation, which has been shown to possess hair follicle-inducing capability. By assaying for endogenous CD133 expression and performing lineage tracing using CD133-CreERT2; ZsGreen1 reporter mice, we find that CD133 is expressed in a subpopulation of DP cells during the growth phase of the murine hair cycle (anagen), but is absent at anagen onset. However, how CD133+ DP cells interact with keratinocytes to induce hair regenerative growth remains unclear. Wnt/β-catenin has long been recognized as a major signaling pathway required for hair follicle morphogenesis, development, and regeneration. Nuclear Wnt/β-catenin activity is observed in the DP during the hair growth phase. Here we show that induced expression of a stabilized form of β-catenin in CD133+ DP cells significantly accelerates spontaneous and depilation-induced hair growth. However, hair follicle regression is not affected in these mutants. Further analysis indicates that CD133+ DP-expressed β-catenin increases proliferation and differentiation of epithelial matrix keratinocytes. Upregulated Wnt/β-catenin activity in CD133+ DP cells also increases the number of proliferating DP cells in each anagen follicle. Our data demonstrate that β-catenin signaling potentiates the capability of CD133+ DP cells to promote postnatal hair growth.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160425PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966972PMC
August 2017

Activating β-catenin signaling in CD133-positive dermal papilla cells increases hair inductivity.

FEBS J 2016 08 11;283(15):2823-35. Epub 2016 Jul 11.

Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, OH, USA.

Bioengineering hair follicles using cells isolated from human tissue remains a difficult task. Dermal papilla (DP) cells are known to guide the growth and cycling activities of hair follicles by interacting with keratinocytes. However, DP cells quickly lose their inductivity during in vitro passaging. Rodent DP cell cultures need external addition of growth factors, including WNT and BMP molecules, to maintain the hair inductive property. CD133 is expressed by a subpopulation of DP cells that are capable of inducing hair follicle formation in vivo. We report here that expression of a stabilized form of β-catenin promoted clonal growth of CD133-positive (CD133+) DP cells in in vitro three-dimensional hydrogel culture while maintaining expression of DP markers, including alkaline phosphatase (AP), CD133, and integrin α8. After a 2-week in vitro culture, cultured CD133+ DP cells with up-regulated β-catenin activity led to an accelerated in vivo hair growth in reconstituted skin compared to control cells. Further analysis showed that matrix cell proliferation and differentiation were significantly promoted in hair follicles when β-catenin signaling was up-regulated in CD133+ DP cells. Our data highlight an important role for β-catenin signaling in promoting the inductive capability of CD133+ DP cells for in vitro expansion and in vivo hair follicle regeneration, which could potentially be applied to cultured human DP cells.
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http://dx.doi.org/10.1111/febs.13784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4975668PMC
August 2016

Beta-catenin is essential for ameloblast movement during enamel development.

Eur J Oral Sci 2016 06 9;124(3):221-7. Epub 2016 Mar 9.

Division of Biosciences, College of Dentistry, Ohio State University, Columbus, OH, USA.

Beta-catenin is a multifunctional protein that plays key roles in cadherin-based cell adherens junctions and in the Wnt signaling pathway. The canonical Wnt/β-catenin pathway can regulate transcription factors that control cell movement/invasion. We investigated whether β-catenin regulates ameloblast movement through canonical Wnt signaling. The morphological and physical properties of enamel were assessed in enamel from control and β-catenin conditional knockout (cKO) mice. Ameloblast-lineage cells (ALC) were used to investigate the potential roles of β-catenin in cell migration and in E-cadherin expression. Compared with controls, incisors from β-catenin cKO mice were short, blunt, and where enamel was present, it was soft and malformed. Scanning electron microscopy revealed a dysplastic rod pattern within the enamel of incisors from β-catenin cKO mice, and Vickers microhardness measurements confirmed that mice with β-catenin ablated from their enamel organ had enamel that was significantly softer than normal. Amelogenesis was disrupted in the absence of β-catenin and the ameloblasts did not differentiate properly. We further demonstrated that migration of ALCs was inhibited in vitro and that E-cadherin expression was significantly up-regulated when ALCs were treated with the β-catenin inhibitor, ICG-001. Beta-catenin ablation causes enamel malformation in mice and this phenotype may occur, in part, by a lack of ameloblast differentiation and/or movement necessary to form the decussating enamel rod structure.
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http://dx.doi.org/10.1111/eos.12261DOI Listing
June 2016

Lhx2 is a direct NF-κB target gene that promotes primary hair follicle placode down-growth.

Development 2016 05 7;143(9):1512-22. Epub 2016 Mar 7.

Department of Signal Transduction in Tumor Cells, Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin 13092, Germany

In the epidermis of mice lacking transcription factor nuclear factor-kappa B (NF-κB) activity, primary hair follicle (HF) pre-placode formation is initiated without progression to proper placodes. NF-κB modulates WNT and SHH signaling at early stages of HF development, but this does not fully account for the phenotypes observed upon NF-κB inhibition. To identify additional NF-κB target genes, we developed a novel method to isolate and transcriptionally profile primary HF placodes with active NF-κB signaling. In parallel, we compared gene expression at the same developmental stage in NF-κB-deficient embryos and controls. This uncovered novel NF-κB target genes with potential roles in priming HF placodes for down-growth. Importantly, we identify Lhx2 (encoding a LIM/homeobox transcription factor) as a direct NF-κB target gene, loss of which replicates a subset of phenotypes seen in NF-κB-deficient embryos. Lhx2 and Tgfb2 knockout embryos exhibit very similar abnormalities in HF development, including failure of the E-cadherin suppression required for follicle down-growth. We show that TGFβ2 signaling is impaired in NF-κB-deficient and Lhx2 knockout embryos and that exogenous TGFβ2 rescues the HF phenotypes in Lhx2 knockout skin explants, indicating that it operates downstream of LHX2. These findings identify a novel NF-κB/LHX2/TGFβ2 signaling axis that is crucial for primary HF morphogenesis, which may also function more broadly in development and disease.
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http://dx.doi.org/10.1242/dev.130898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514410PMC
May 2016

Secrets of the Hair Follicle: Now on Your iPhone.

Authors:
Sarah E Millar

Dev Cell 2015 Sep;34(5):488-90

Departments of Dermatology and Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Skin development requires communication between epithelial and mesenchymal cells, melanocytes, and neurons. In this issue of Developmental Cell, Sennett et al. (2015) shed new light on these mechanisms by simultaneously profiling multiple different cell types in embryonic mouse skin at the onset of hair follicle formation.
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http://dx.doi.org/10.1016/j.devcel.2015.08.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573398PMC
September 2015

β-Catenin Signaling Biases Multipotent Lingual Epithelial Progenitors to Differentiate and Acquire Specific Taste Cell Fates.

PLoS Genet 2015 May 28;11(5):e1005208. Epub 2015 May 28.

Department of Cell & Developmental Biology, and the Rocky Mountain Taste & Smell Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.

Continuous taste bud cell renewal is essential to maintain taste function in adults; however, the molecular mechanisms that regulate taste cell turnover are unknown. Using inducible Cre-lox technology, we show that activation of β-catenin signaling in multipotent lingual epithelial progenitors outside of taste buds diverts daughter cells from a general epithelial to a taste bud fate. Moreover, while taste buds comprise 3 morphological types, β-catenin activation drives overproduction of primarily glial-like Type I taste cells in both anterior fungiform (FF) and posterior circumvallate (CV) taste buds, with a small increase in Type II receptor cells for sweet, bitter and umami, but does not alter Type III sour detector cells. Beta-catenin activation in post-mitotic taste bud precursors likewise regulates cell differentiation; forced activation of β-catenin in these Shh+ cells promotes Type I cell fate in both FF and CV taste buds, but likely does so non-cell autonomously. Our data are consistent with a model where β-catenin signaling levels within lingual epithelial progenitors dictate cell fate prior to or during entry of new cells into taste buds; high signaling induces Type I cells, intermediate levels drive Type II cell differentiation, while low levels may drive differentiation of Type III cells.
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http://dx.doi.org/10.1371/journal.pgen.1005208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447363PMC
May 2015

Deficient Wnt signalling triggers striatal synaptic degeneration and impaired motor behaviour in adult mice.

Nat Commun 2014 Oct 16;5:4992. Epub 2014 Oct 16.

Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.

Synapse degeneration is an early and invariant feature of neurodegenerative diseases. Indeed, synapse loss occurs prior to neuronal degeneration and correlates with the symptom severity of these diseases. However, the molecular mechanisms that trigger synaptic loss remain poorly understood. Here we demonstrate that deficient Wnt signalling elicits synaptic degeneration in the adult striatum. Inducible expression of the secreted Wnt antagonist Dickkopf1 (Dkk1) in adult mice (iDkk1) decreases the number of cortico-striatal glutamatergic synapses and of D1 and D2 dopamine receptor clusters. Synapse loss occurs in the absence of axon retraction or cell death. The remaining excitatory terminals contain fewer synaptic vesicles and have a reduced probability of evoked transmitter release. IDkk1 mice show impaired motor coordination and are irresponsive to amphetamine. These studies identify Wnts as key endogenous regulators of synaptic maintenance and suggest that dysfunction in Wnt signalling contributes to synaptic degeneration at early stages in neurodegenerative diseases.
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http://dx.doi.org/10.1038/ncomms5992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4218967PMC
October 2014

CD133 expression correlates with membrane beta-catenin and E-cadherin loss from human hair follicle placodes during morphogenesis.

J Invest Dermatol 2015 Jan 10;135(1):45-55. Epub 2014 Jul 10.

Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address:

Genetic studies suggest that the major events of human hair follicle development are similar to those in mice, but detailed analyses of this process are lacking. In mice, hair follicle placode "budding" is initiated by invagination of Wnt-induced epithelium into the underlying mesenchyme. Modification of adherens junctions (AJs) is clearly required for budding. Snail-mediated downregulation of AJ component E-cadherin is important for placode budding in mice. Beta-catenin, another AJ component, has been more difficult to study owing to its essential functions in Wnt signaling, a prerequisite for hair follicle placode induction. Here, we show that a subset of human invaginating hair placode cells expresses the stem cell marker CD133 during early morphogenesis. CD133 associates with membrane beta-catenin in early placodes, and its continued expression correlates with loss of beta-catenin and E-cadherin from the cell membrane at a time when E-cadherin transcriptional repressors Snail and Slug are not implicated. Stabilization of CD133 via anti-CD133 antibody treatment of human fetal scalp explants depresses beta-catenin and E-cadherin membrane localization. We discuss this unique correlation and suggest a hypothetical model whereby CD133 promotes morphogenesis in early hair follicle placodes through the localized removal of membrane beta-catenin proteins and subsequent AJ dissolution.
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http://dx.doi.org/10.1038/jid.2014.292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465595PMC
January 2015

Distinct functions for Wnt/β-catenin in hair follicle stem cell proliferation and survival and interfollicular epidermal homeostasis.

Cell Stem Cell 2013 Dec;13(6):720-33

Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.

Wnt/β-catenin signaling is a central regulator of adult stem cells. Variable sensitivity of Wnt reporter transgenes, β-catenin's dual roles in adhesion and signaling, and hair follicle degradation and inflammation resulting from broad deletion of epithelial β-catenin have precluded clear understanding of Wnt/β-catenin's functions in adult skin stem cells. By inducibly deleting β-catenin globally in skin epithelia, only in hair follicle stem cells, or only in interfollicular epidermis and comparing the phenotypes with those caused by ectopic expression of the Wnt/β-catenin inhibitor Dkk1, we show that this pathway is necessary for hair follicle stem cell proliferation. However, β-catenin is not required within hair follicle stem cells for their maintenance, and follicles resume proliferating after ectopic Dkk1 has been removed, indicating persistence of functional progenitors. We further unexpectedly discovered a broader role for Wnt/β-catenin signaling in contributing to progenitor cell proliferation in nonhairy epithelia and interfollicular epidermis under homeostatic, but not inflammatory, conditions.
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http://dx.doi.org/10.1016/j.stem.2013.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3900235PMC
December 2013

Canonical wnt signaling is required for pancreatic carcinogenesis.

Cancer Res 2013 Aug 12;73(15):4909-22. Epub 2013 Jun 12.

Department of Surgery, University of Michigan Medical School, 1500 E Medical Center Drive, Ann Arbor, MI 48109, USA.

Wnt ligand expression and activation of the Wnt/β-catenin pathway have been associated with pancreatic ductal adenocarcinoma, but whether Wnt activity is required for the development of pancreatic cancer has remained unclear. Here, we report the results of three different approaches to inhibit the Wnt/β-catenin pathway in a established transgenic mouse model of pancreatic cancer. First, we found that β-catenin null cells were incapable of undergoing acinar to ductal metaplasia, a process associated with development of premalignant pancreatic intraepithelial neoplasia lesions. Second, we addressed the specific role of ligand-mediated Wnt signaling through inducible expression of Dkk1, an endogenous secreted inhibitor of the canonical Wnt pathway. Finally, we targeted the Wnt pathway with OMP-18R5, a therapeutic antibody that interacts with multiple Frizzled receptors. Together, these approaches showed that ligand-mediated activation of the Wnt/β-catenin pathway is required to initiate pancreatic cancer. Moreover, they establish that Wnt signaling is also critical for progression of pancreatic cancer, a finding with potential therapeutic implications.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-4384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763696PMC
August 2013

Fgf9 from dermal γδ T cells induces hair follicle neogenesis after wounding.

Nat Med 2013 Jul 2;19(7):916-23. Epub 2013 Jun 2.

Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Understanding molecular mechanisms for regeneration of hair follicles provides new opportunities for developing treatments for hair loss and other skin disorders. Here we show that fibroblast growth factor 9 (Fgf9), initially secreted by γδ T cells, modulates hair follicle regeneration after wounding the skin of adult mice. Reducing Fgf9 expression decreases this wound-induced hair neogenesis (WIHN). Conversely, overexpression of Fgf9 results in a two- to threefold increase in the number of neogenic hair follicles. We found that Fgf9 from γδ T cells triggers Wnt expression and subsequent Wnt activation in wound fibroblasts. Through a unique feedback mechanism, activated fibroblasts then express Fgf9, thus amplifying Wnt activity throughout the wound dermis during a crucial phase of skin regeneration. Notably, humans lack a robust population of resident dermal γδ T cells, potentially explaining their inability to regenerate hair after wounding. These findings highlight the essential relationship between the immune system and tissue regeneration. The importance of Fgf9 in hair follicle regeneration suggests that it could be used therapeutically in humans.
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http://dx.doi.org/10.1038/nm.3181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4054871PMC
July 2013