• 11 2015

    The Ganesan lab has published their work on Tyrosinase regulation of melanosome maturation in PLoS One

    The mechanisms that lead to variation in human skin and hair color are not fully understood. To better understand the molecular control of skin and hair color variation, we modulated the expression of Tyrosinase (Tyr), which controls the rate-limiting step of melanogenesis, by expressing a single-copy, tetracycline-inducible shRNA against Tyr in mice. Moderate depletion of TYR was sufficient to alter the appearance of the mouse coat in black, agouti, and yellow coat color backgrounds, even though TYR depletion did not significantly inhibit accumulation of melanin within the mouse hair. Ultra-structural studies revealed that the reduction of Tyr inhibited the accumulation of terminal melanosomes, and inhibited the expression of genes that regulate melanogenesis. These results indicate that color in skin and hair is determined not only by the total amount of melanin within the hair, but also by the relative accumulation of mature melanosomes. Read More

  • 11 2015

    The Dai lab has published their work on modeling Ovol2-Zeb1 epithelial and mesenchymal states in PLoS Computational Biology

    Reversible epithelial-to-mesenchymal transition (EMT) is central to tissue development, epithelial stemness, and cancer metastasis. While many regulatory elements have been identified to induce EMT, the complex process underlying such cellular plasticity remains poorly understood. Utilizing a systems biology approach integrating modeling and experiments, we found multiple intermediate states contributing to EMT and that the robustness of the transitions is modulated by transcriptional factor Ovol2. In particular, we obtained evidence for a mutual inhibition relationship between Ovol2 and EMT inducer Zeb1, and observed that adding this regulation generates a novel four-state system consisting of two distinct intermediate phenotypes that differ in differentiation propensities and are favored in different environmental conditions. We identified epithelial cells that naturally exist in an intermediate state with bidirectional differentiation potential, and found the balance between EMT-promoting and -inhibiting factors to be critical in achieving and selecting between intermediate states. Our analysis suggests a new design principle in controlling cellular plasticity through multiple intermediate cell fates and underscores the critical involvement of Ovol2 and its associated molecular regulations. Read More

  • 10 2015

    UC Irvine Stem Cell Symposium on skin stem cells

    Wednesday, October 14th 2015 marks Stem Cell Awareness Day, which brings together organizations and individuals around the world working to ensure that we realize the benefits of one of the most promising fields of science in our time. The day is a unique global opportunity to foster greater understanding about stem cell research and the range of potential applications for disease and injury.

    For the millions of people around the world who suffer from incurable diseases and injury, Stem Cell Awareness Day is a day to celebrate the scientific advances made to-date and be hopeful of what is yet to come. UCI will be hosting a Symposium on Skin Stem Cells on October 28 at the UC Irvine Gross Hall to highlight and celebrate the amazing work to understand and translate skin stem cells to benefit human health. This amazing symposium will feature lectures on skin stem cells and cancer stem cells, with an emphasis of their basic and translational challenges and opportunities. Please register here to reserve your spot as space is limited.

  • 9 2015

    PASPCR conference on melanocytes

    The 2015 Panamerican Society for Pigment Cell Research (PASPCR) will be held September 27-30 at the UC Irvine Medical Center. This annual international meeting brings together physicians, scientists, and patients and promises to be a scientifically and medically valuable (and fun) event. The underlying theme of this year's conference is "The Melanocyte and Its Multiple Niches: New Biology in Health and Disease". A prestigious group of speakers and conference leaders have been assembled for the meeting. Our own Anand Ganesan is serving as Co-Chair of the conference which plans to have major plenary sessions in the following areas: The Developmental and Stem Cell Biology of Melanocytes and its Environment, Understanding Internal Melanin, Neuromelanin and the Melanosome, UV and Non-UV Pathways in Melanoctyes and Melanoma, Advances in Diagnostics: Imaging and Genomics, and New Directions in the Management of Melanoma.

  • 9 2015

    The Plikus lab has published a review on regeneration in wound-induced hair follicle neogenesis in Regeneration

    Wound induced hair follicle neogenesis (WIHN) describes a regenerative phenomenon in adult mammalian skin, wherein fully functional hair follicles regenerate de novo in the center of large excisional wounds. Originally described in rats, rabbits, sheep, and humans in 1940–60, the WIHN phenomenon was reinvestigated in mice only recently. The process of de novo hair regeneration largely duplicates the morphological and signaling features of normal embryonic hair development. Similar to hair development, WIHN critically depends on the activation of canonical WNT signaling. However, unlike hair development, WNT activation in WIHN is dependent on Fgf9 signaling generated by the immune system’s gamma delta (γδ) T cells. The cellular bases of WIHN remain to be fully characterized, however, the available evidence leaves open the possibility for a blastema-like mechanism, wherein epidermal and/or dermal wound cells undergo epigenetic reprogramming toward a more plastic, embryonic-like state. De novo hair follicles do not regenerate from preexisting hair-fated bulge stem cells. This suggests that hair neogenesis is not driven by preexisting lineage-restricted progenitors, as is the case for amputation-induced mouse digit tip regeneration, but rather may require a blastema-like mechanism. The WIHN model is characterized by several intriguing features, which await further explanation. These include: (i) minimum wound size requirement for activating neogenesis, (ii) restriction of hair neogenesis to the wound’s center, (iii) imperfect patterning outcomes, both in terms of neogenic hair positioning within the wound and in terms of their orientation. Future inquires into the WIHN process, made possible by a wide array of the available skin-specific genetic tools, will undoubtedly expand our understanding of the regeneration mechanisms in adult mammals. Read More

  • 9 2015

    The Plikus lab has published a guide to studying human hair follicle cycling in vivo in the Journal of Investigative Dermatology

    Hair follicles (HFs) undergo life-long cyclical transformations, progressing through stages of rapid growth (anagen), regression (catagen), and relative “quiescence” (telogen). Since HF cycling abnormalities underlie many human hair growth disorders, the accurate classification of individual cycle stages within skin biopsies is clinically important and essential for hair research. For preclinical human hair research purposes, human scalp skin can be xenografted onto immunocompromised mice to study human HF cycling and manipulate long-lasting anagen in vivo. While available for mice, a comprehensive guide on how to recognize different human hair cycle stages in vivo is lacking. Here, we present such a guide, which uses objective, well-defined, and reproducible criteria and integrates simple morphological indicators with advanced, (immuno)-histochemical markers. This guide also characterizes human HF cycling in xenografts and highlights the utility of this model for in vivo hair research. Detailed schematic drawings and representative micrographs provide examples of how best to identify human HF stages, even in sub-optimally sectioned tissue, and practical recommendations are given for designing human-on-mouse hair cycle experiments. Thus, this guide seeks to offer a benchmark for human hair cycle stage classification, for both hair research experts and newcomers to the field. Read More

  • 8 2015

    The Atwood lab has published their work on genetic diversity in basal cell carcinoma in the Journal of Investigative Dermatology

    Genomic analysis by our group and others have revealed that basal cell carcinomas (BCCs) carry a high frequency of non-silent mutations, yet how these mutations confer selective tumor growth without deleterious effects remains poorly understood. Here, we find that Smoothened (SMO) mutations are frequently found across many cancers with drug-resistant BCCs bearing the highest rate of recurrent mutations at 66%. We identify 28 mutations in SMO that were either recurrent, overlap with the COSMIC database, or were region-specific and interrogated their ability to promote HH signaling. We find that each mutation exerts either neutral or negative effects on HH signaling with a subset of mutations abolishing SMO function. This was surprising as nearly half of the residues lie in the pivot regions or the ligand binding pocket of SMO, which control protein activity and binding of SMO inhibitors, respectively. Our data supports a model where tumors are permissive to genetic mutations, generating many genetically diverse clones that compete as a way to grow. As we expand our use of high-throughput sequencing of tumors for personalized medicine, our results present a cautionary tale to functionally validate any mutation before concluding their ability to exert oncogenic effects. Read More

  • 8 2015

    The Dai lab has published their work on Akt regulating the Wnt coactivator and chromatin effector Pygo2 in the Journal of Biological Chemistry

    Pygopus 2 (Pygo2/PYGO2) is an evolutionarily conserved coactivator and chromatin effector in the Wnt/β-catenin signaling pathway that regulates cell growth and differentiation in various normal and malignant tissues. Although PYGO2 is highly overexpressed in a number of human cancers, the molecular mechanism underlying its deregulation is largely unknown. Here we report that Pygo2 protein is degraded through the ubiquitin/proteasome pathway and is posttranslationally stabilized through phosphorylation by activated phosphatidylinositol 3-kinase/Akt signaling. Specifically, Pygo2 is stabilized upon inhibition of the proteasome, and its intracellular level is regulated by Cullin 4 (Cul4) and DNA damage-binding protein 1 (DDB1), components of the Cul4-DDB1 E3 ubiquitin ligase complex. Furthermore, Pygo2 is phosphorylated at multiple residues, and Akt-mediated phosphorylation at serine 48 leads to its decreased ubiquitylation and increased stability. Finally, we provide evidence that Akt and its upstream growth factors act in parallel with Wnt to stabilize Pygo2. Taken together, our findings highlight chromatin regulator Pygo2 as a common node downstream of oncogenic Wnt and Akt signaling pathways and underscore posttranslational modification, particularly phosphorylation and ubiquitylation, as a significant mode of regulation of Pygo2 protein expression. Read More

  • 6 2015

    The Plikus and Andersen labs have published a review on the skin circadian clock in the Journal of Biological Rhythms

    Historically, work on peripheral circadian clocks has been focused on organs and tissues that have prominent metabolic functions, such as the liver, fat, and muscle. In recent years, skin has emerged as a model for studying circadian clock regulation of cell proliferation, stem cell functions, tissue regeneration, aging, and carcinogenesis. Morphologically, skin is complex, containing multiple cell types and structures, and there is evidence for a functional circadian clock in most, if not all, of its cell types. Despite the complexity, skin stem cell populations are well defined, experimentally tractable, and exhibit prominent daily cell proliferation cycles. Hair follicle stem cells also participate in recurrent, long-lasting cycles of regeneration: the hair growth cycles. Among other advantages of skin is a broad repertoire of available genetic tools enabling the creation of cell type-specific circadian mutants. Also, due to the accessibility of skin, in vivo imaging techniques can be readily applied to study the circadian clock and its outputs in real time, even at the single-cell level. Skin provides the first line of defense against many environmental and stress factors that exhibit dramatic diurnal variations such as solar ultraviolet (UV) radiation and temperature. Studies have already linked the circadian clock to the control of UVB-induced DNA damage and skin cancers. Due to the important role that skin plays in the defense against microorganisms, it also represents a promising model system to further explore the role of the clock in the regulation of the body's immune functions. To that end, recent studies have already linked the circadian clock to psoriasis, one of the most common immune-mediated skin disorders. Skin also provides opportunities to interrogate the clock regulation of tissue metabolism in the context of stem cells and regeneration. Furthermore, many animal species feature prominent seasonal hair molt cycles, offering an attractive model for investigating the role of the clock in seasonal organismal behaviors. Read More

  • 4 2015

    The Plikus lab has published their work on organ-level quorum sensing in hair stem cell populations in Cell

    Coordinated organ behavior is crucial for an effective response to environmental stimuli. By studying regeneration of hair follicles in response to patterned hair plucking, we demonstrate that organ-level quorum sensing allows coordinated responses to skin injury. Plucking hair at different densities leads to a regeneration of up to five times more neighboring, unplucked resting hairs, indicating activation of a collective decision-making process. Through data modeling, the range of the quorum signal was estimated to be on the order of 1 mm, greater than expected for a diffusible molecular cue. Molecular and genetic analysis uncovered a two-step mechanism, where release of CCL2 from injured hairs leads to recruitment of TNF-α-secreting macrophages, which accumulate and signal to both plucked and unplucked follicles. By coupling immune response with regeneration, this mechanism allows skin to respond predictively to distress, disregarding mild injury, while meeting stronger injury with full-scale cooperative activation of stem cells. Read More

  • 4 2015

    The Plikus lab has published a review on regenerative metamorphosis in hairs and feathers in Experimental Dermatology

    Present-day hairs and feathers are marvels of biological engineering perfected over 200 million years of convergent evolution. Prominently, both follicle types coevolved regenerative cycling, wherein active filament making (anagen) is intermitted by a phase of relative quiescence (telogen). Such regenerative cycling enables follicles to “reload” their morphogenetic program and make qualitatively different filaments in the consecutive cycles. Indeed, many species of mammals and birds undergo regenerative metamorphosis, prominently changing their integument between juvenile and adult forms. This phenomenon is inconspicuous in mice, which led to the conventional perception that hair type is hardwired during follicle morphogenesis and cannot switch. A series of recent works by Chi and Morgan change this perception, and show that many mouse follicles naturally switch hair morphologies, for instance from “wavy” zigzag to straight awl, in the second growth cycle. A series of observations and genetic experiments show that back and forth hair type switching depends on the number of cells in the follicle's dermal papilla, with the critical threshold being around 40-50 cells. Pigmentation is another parameter that hair and feather follicles can reload between cycles, and even midway through anagen. Recent works show that hair and feather pigmentation “printing” programs coevolved to rely on pulsed expression of Agouti, a melanocortin receptor-1 antagonist, in the follicular mesenchyme. Here, we discuss broader implications of hair and feather regenerative plasticity. Read More

  • 3 2015

    The Atwood lab has published their work on describing how the majority of basal cell carcinomas aquire drug resistance in Cancer Cell

    Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition. These genetic alterations suggest that SMO functions similarly to other class A GPCRs despite less than 10% sequence identity. In the presence of a SMO inhibitor, tumor cells containing both classes of SMO mutants effectively compete against cells containing wild type SMO. Finally, we show that both classes of SMO variants respond to aPKC-ι/λ or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists. Read More

  • 3 2015

    The Plikus lab has published a review on the epigenetic control of skin and hair regeneration after wounding in Experimental Dermatology

    Skin wound healing is a complex regenerative phenomenon that can result in hair follicle neogenesis. Skin regeneration requires significant contribution from the immune system and involves substantial remodelling of both epidermal and dermal compartments. In this viewpoint, we consider epigenetic regulation of reepithelialization, dermal restructuring and hair neogenesis. Because little is known about the epigenetic control of these events, we have drawn upon recent epigenetic mapping and functional studies of homeostatic skin maintenance, epithelial-mesenchymal transition in cancer, and new works on regenerative dermal cell lineages and the epigenetic events that may shape their conversion into myofibroblasts. Finally, we speculate on how these various healing components might converge for wound-induced hair follicle neogenesis. Read More

  • 1 2015

    The Plikus lab has published their work on dermal adipocytes protecting against skin infections in Science

    Adipocytes have been suggested to be immunologically active, but their role in host defense is unclear. We observed rapid proliferation of preadipocytes and expansion of the dermal fat layer after infection of the skin by Staphylococcus aureus. Impaired adipogenesis resulted in increased infection as seen in Zfp423(nur12) mice or in mice given inhibitors of peroxisome proliferator-activated receptor γ. This host defense function was mediated through the production of cathelicidin antimicrobial peptide from adipocytes because cathelicidin expression was decreased by inhibition of adipogenesis, and adipocytes from Camp(-/-) mice lost the capacity to inhibit bacterial growth. Together, these findings show that the production of an antimicrobial peptide by adipocytes is an important element for protection against S. aureus infection of the skin. Read More

  • 1 2015

    The Andersen lab has published their work on single-cell detection of metabolic oscillations in Cell Reports

    Through the use of bulk measurements in metabolic organs, the circadian clock was shown to play roles in organismal energy homeostasis. However, the relationship between metabolic and circadian oscillations has not been studied in vivo at a single-cell level. Also, it is unknown whether the circadian clock controls metabolism in stem cells. We used a sensitive, noninvasive method to detect metabolic oscillations and circadian phase within epidermal stem cells in live mice at the single-cell level. We observe a higher NADH/NAD+ ratio, reflecting an increased glycolysis/oxidative phosphorylation ratio during the night compared to the day. Furthermore, we demonstrate that single-cell metabolic heterogeneity within the basal cell layer correlates with the circadian clock and that diurnal fluctuations in NADH/NAD+ ratio are Bmal1 dependent. Our data show that, in proliferating stem cells, the circadian clock coordinates activities of oxidative phosphorylation and glycolysis with DNA synthesis, perhaps as a protective mechanism against genotoxicity. Read More

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