40 results found
Contessi Negrini N, Angelova Volponi A, Higgins CA, et al., 2021, Scaffold-based developmental tissue engineering strategies for ectodermal organ regeneration, Materials Today Bio, Vol: 10, Pages: 1-22, ISSN: 2590-0064
Tissue engineering (TE) is a multidisciplinary research field aiming at the regeneration, restoration, or replacement of damaged tissues and organs. Classical TE approaches combine scaffolds, cells and soluble factors to fabricate constructs mimicking the native tissue to be regenerated. However, to date, limited success in clinical translations has been achieved by classical TE approaches, because of the lack of satisfactory biomorphological and biofunctional features of the obtained constructs. Developmental TE has emerged as a novel TE paradigm to obtain tissues and organs with correct biomorphology and biofunctionality by mimicking the morphogenetic processes leading to the tissue/organ generation in the embryo. Ectodermal appendages, for instance, develop in vivo by sequential interactions between epithelium and mesenchyme, in a process known as secondary induction. A fine artificial replication of these complex interactions can potentially lead to the fabrication of the tissues/organs to be regenerated. Successful developmental TE applications have been reported, in vitro and in vivo, for ectodermal appendages such as teeth, hair follicles and glands. Developmental TE strategies require an accurate selection of cell sources, scaffolds and cell culture configurations to allow for the correct replication of the in vivo morphogenetic cues. Herein, we describe and discuss the emergence of this TE paradigm by reviewing the achievements obtained so far in developmental TE 3D scaffolds for teeth, hair follicles, and salivary and lacrimal glands, with particular focus on the selection of biomaterials and cell culture configurations.
Stewart S, Tenenbaum O, Masouros S, et al., 2020, Fracture non-union rates across a century of war: a systematic review of the literature, BMJ Military Health, Vol: 166, Pages: 271-276, ISSN: 2633-3767
IntroductionFractures have been a common denominator of the injury patterns observed over the past century of warfare. The fractures typified by the blast and ballistic injuries of war lead to high rates of bone loss, soft tissue injury and infection, greatly increasing the likelihood of non-union. Despite this, no reliable treatment strategy for non-union exists. This literature review aims to explore the rates of non-union across a century of conflict and war, in order to determine whether our ability to heal the fractures of war has improved.MethodsA systematic review of the literature was conducted, evaluating the rates of union in fractures sustained in a combat environment over a one hundred year period. Only those fractures sustained through a ballistic or blast mechanism were included. The review was in accordance with the Preferred Items for Systematic Reviews and Meta-Analyses (PRISMA). Quality and bias assessment was also undertaken. ResultsThirty studies met the inclusion criteria, with a total of 3232 fractures described across fifteen different conflicts from the period 1919-2019. Male subjects made up 96% of cases, and tibial fractures predominated (39%). The lowest fracture union rate observed in a series was 50%. Linear regression analysis demonstrated that increasing years had no statistically significant impact on union rate.ConclusionFailure to improve fracture union rates is likely a result of numerous factors, including greater use of blast weaponry and better survivability of casualties. Finding novel strategies to promote fracture healing is a key defence research priority, in order to improve the rates of fractures sustained in a combat environment.
Topouzi H, Boyle C, Williams G, et al., 2020, Harnessing the secretome of hair follicle fibroblasts to accelerate ex vivo healing of human skin wounds, Journal of Investigative Dermatology, Vol: 140, Pages: 1075-1084.e11, ISSN: 0022-202X
In skin homeostasis, dermal fibroblasts are responsible for coordinating the migration and differentiation of overlying epithelial keratinocytes. As hairy skin heals faster than nonhairy skin, we took bio-inspiration from the follicle and hypothesized that follicular fibroblasts would accelerate skin re-epithelialization after injury faster than interfollicular fibroblasts. Using both in vitro and ex vivo models of human skin wound closure, we found that hair follicle dermal papilla fibroblasts could accelerate closure of in vitro scratch wounds by 1.8-fold and epithelial growth capacity by 1.5-fold compared with controls (P < 0.05). We used a cytokine array to determine how the dermal papilla fibroblasts were eliciting this effect and identified two cytokines, sAXL and CCL19, that are released at significantly higher levels by follicular fibroblasts than by interfollicular subtypes. Using sAXL and CCL19 individually, we found that they could also increase closure of epithelial cells in a scratch wound by 1.2- and 1.5-fold, respectively, compared with controls (P < 0.05). We performed an unbiased transcriptional analysis, combined with pathway analysis, and postulate that sAXL accelerates wound closure by promoting migration and inhibiting epithelial differentiation of skin keratinocytes. Long term, we believe these results can be exploited to accelerate wound closure of human skin in vivo.
Wang EC, Higgins CA, 2020, Immune cell regulation of the hair cycle, Experimental Dermatology, Vol: 29, Pages: 322-333, ISSN: 0906-6705
The ability to manipulate the mammalian hair cycle will lead to novel therapies and strategies to combat all forms of alopecia. Thus, in addition to the epithelial-mesenchymal interactions in the hair follicle, niche and microenvironmental signals that accompany the phases of growth, regression and rest need to be scrutinized. Immune cells are well-described in skin homeostasis and wound healing, and have recently been shown to play an important role in the mammalian hair cycle. In this review, we will summarize our current knowledge of the role of immune cells in hair cycle control, and discuss their relevance to human hair cycling disorders. Increased attention to this aspect of the hair cycle will provide new avenues to manipulate hair regeneration in humans, and provide better insight into developing better ex vivo models of hair growth.
Boyle C, Carpanen D, Pandelani T, et al., 2020, Lateral pressure equalisation as a principle for designing support surfaces to prevent deep tissue pressure ulcers, PLoS One, Vol: 15, ISSN: 1932-6203
When immobile or neuropathic patients are supported by beds or chairs, their soft tissues undergo deformations that can cause pressure ulcers. Current support surfaces that redistribute under-body pressures at vulnerable body sites have not succeeded in reducing pressure ulcer prevalence. Here we show that adding a supporting lateral pressure can counter-act the deformations induced by under-body pressure, and that this ‘pressure equalisation’ approach is a more effective way to reduce ulcer-inducing deformations than current approaches based on redistributing under-body pressure.A finite element model of the seated pelvis predicts that applying a lateral pressure to the soft tissue reduces peak von Mises stress in the deep tissue by a factor of 2.4 relative to a standard cushion (from 113 kPa to 47 kPA) — a greater effect than that achieved by using a more conformable cushion, which reduced von Mises stress to 75 kPa. Combining both a conformable cushion and lateral pressure reduced peak von Mises stresses to 25 kPa. The ratio of peak lateral pressure to peak under-body pressure was shown to regulate deep tissue stress better than under-body pressure alone. By optimising the magnitude and position of lateral pressure, tissue deformations can be reduced to that induced when suspended in a fluid.Our results explain the lack of efficacy in current support surfaces and suggest a new approach to designing and evaluating support surfaces: ensuring sufficient lateral pressure is applied to counter-act under-body pressure.
Bone is one of the most highly adaptive tissues in the body, possessing the capability to alter its morphology and function in response to stimuli in its surrounding environment. The ability of bone to sense and convert external mechanical stimuli into a biochemical response, which ultimately alters the phenotype and function of the cell, is described as mechanotransduction. This review aims to describe the fundamental physiology and biomechanisms that occur to induce osteogenic adaptation of a cell following application of a physical stimulus. Considerable developments have been made in recent years in our understanding of how cells orchestrate this complex interplay of processes, and have become the focus of research in osteogenesis. We will discuss current areas of preclinical and clinical research exploring the harnessing of mechanotransductive properties of cells and applying them therapeutically, both in the context of fracture healing and de novo bone formation in situations such as nonunion.
Limbu S, Higgins CA, 2020, Isolating Dermal Papilla Cells from Human Hair Follicles Using Microdissection and Enzyme Digestion., Methods Mol Biol, Vol: 2154, Pages: 91-103
The dermal papilla (DP) is a cluster of mesenchymal cells located at the bottom of the hair follicle. Cells within the DP interact with numerous other cell types within the follicle, including epithelial stem cells, matrix cells, and melanocytes, regulating their function. The diameter of the DP is directly proportional to the width of the hair shaft, and a decrease in both cell number and DP size is observed in hair loss conditions such as androgenetic alopecia. Conversely, microdissected ex vivo DP can instruct growth of de novo hair follicles. The study of DP cells and their role in human hair growth is often hampered by the technical challenge of DP isolation and culture. Here we describe a method used within our research group for isolating DP from human hair follicles.
Boyle C, Plotczyk M, Fayos Villalta S, et al., 2019, Morphology and composition play distinct and complementary roles in the tolerance of plantar skin to mechanical load, Science Advances, Vol: 5, Pages: 1-13, ISSN: 2375-2548
Plantar skin on the soles of the feet has a distinct morphology and composition that is thought to enhance its tolerance to mechanical loads, although the individual contributions of morphology and composition have never been quantified. Here, we combine multiscale mechanical testing and computational models of load bearing to quantify the mechanical environment of both plantar and nonplantar skin under load. We find that morphology and composition play distinct and complementary roles in plantar skin’s load tolerance. More specifically, the thick stratum corneum provides protection from stress-based injuries such as skin tears and blisters, while epidermal and dermal compositions provide protection from deformation-based injuries such as pressure ulcers. This work provides insights into the roles of skin morphology and composition more generally and will inform the design of engineered skin substitutes as well as the etiology of skin injury.
Al Sulaiman D, Chang JYH, Bennett NR, et al., 2019, Hydrogel-coated microneedle arrays for minimally invasive sampling and sensing of specific circulating nucleic acids from skin interstitial fluid, ACS Nano, Vol: 13, Pages: 9620-9628, ISSN: 1936-0851
Minimally invasive technologies that can sample and detect cell-free nucleic acid biomarkers from liquid biopsies have recently emerged as clinically useful for early diagnosis of a broad range of pathologies, including cancer. Although blood has so far been the most commonly interrogated bodily fluid, skin interstitial fluid has been mostly overlooked despite containing the same broad variety of molecular biomarkers originating from cells and surrounding blood capillaries. Emerging technologies to sample this fluid in a pain-free and minimally-invasive manner often take the form of microneedle patches. Herein, we developed microneedles that are coated with an alginate–peptide nucleic acid hybrid material for sequence-specific sampling, isolation, and detection of nucleic acid biomarkers from skin interstitial fluid. Characterized by fast sampling kinetics and large sampling capacity (∼6.5 μL in 2 min), this platform technology also enables the detection of specific nucleic acid biomarkers either on the patch itself or in solution after light-triggered release from the hydrogel. Considering the emergence of cell-free nucleic acids in bodily fluids as clinically informative biomarkers, platform technologies that can detect them in an automated and minimally invasive fashion have great potential for personalized diagnosis and longitudinal monitoring of patient-specific disease progression.
Plotczyk M, Higgins C, 2019, Skin biology, Biomaterials for Skin Repair and Regeneration, Publisher: Woodhead Publishing, ISBN: 9780081025475
With a strong focus on materials, engineering, and application, this book is a valuable resource for materials scientists, skin biologists, and bioengineers with an interest in tissue engineering, regeneration, and repair of skin.
Boyle CJ, Carpanen D, Pandelani T, et al., 2019, Lateral pressure equalisation as a principle for designing support surfaces to prevent deep tissue pressure ulcers, Publisher: Cold Spring Harbor Laboratory
<jats:title>Abstract</jats:title><jats:p>When immobile or neuropathic patients are supported by beds or chairs, their soft tissues undergo deformations that can cause pressure ulcers. Current support surfaces that redistribute under-body pressures at vulnerable body sites have not succeeded in reducing pressure ulcer prevalence. Here we show that adding a supporting lateral pressure can counter-act the deformations induced by under-body pressure, and that this ‘pressure equalisation’ approach is a more effective way to reduce ulcer-inducing deformations than current approaches based on redistributing under-body pressure.</jats:p><jats:p>A finite element model of the seated pelvis predicts that applying a lateral pressure to the soft tissue reduces peak von Mises stress in the deep tissue by a factor of 2.4 relative to a standard cushion — a greater effect than that achieved by using a more conformable cushion. The ratio of peak lateral pressure to peak under-body pressure was shown to regulate deep tissue stress better than under-body pressure alone. By optimising the magnitude and position of lateral pressure, tissue deformations can be reduced to that induced when suspended in a fluid.</jats:p><jats:p>Our results explain the lack of efficacy in current support surfaces, and suggest a new approach to designing and evaluating support surfaces: ensuring sufficient lateral pressure is applied to counter-act under-body pressure.</jats:p>
Logan N, Camman M, Williams G, et al., 2018, Demethylation of ITGAV accelerates osteogenic differentiation in a blast-induced heterotopic ossification in vitro cell culture model, BONE, Vol: 117, Pages: 149-160, ISSN: 8756-3282
Trauma-induced heterotopic ossification is an intriguing phenomenon involving the inappropriate ossification of soft tissues within the body such as the muscle and ligaments. This inappropriate formation of bone is highly prevalent in those affected by blast injuries. Here, we developed a simplified cell culture model to evaluate the molecular events involved in heterotopic ossification onset that arise from the shock wave component of the disease. We exposed three subtypes of human mesenchymal cells in vitro to a single, high-energy shock wave and observed increased transcription in the osteogenic master regulators, Runx2 and Dlx5, and significantly accelerated cell mineralisation. Reduced representation bisulfite sequencing revealed that the shock wave altered methylation of gene promoters, leading to opposing changes in gene expression. Using a drug to target ITGAV, whose expression was perturbed by the shock wave, we found that we could abrogate the deposition of mineral in our model. These findings show how new therapeutics for the treatment of heterotopic ossification can be identified using cell culture models.
Liu J, Higgins C, Whitehouse C, et al., 2018, Hair follicle dermal cells support expansion of murine and human embryonic and induced pluripotent stem cells, and promote haematopoiesis in mouse cultures, Stem Cells International, Vol: 2018, ISSN: 1687-9678
In the hair follicle, the dermal papilla (DP) and dermal sheath (DS) support and maintainproliferation and differentiation of the epithelial stem cells that produce the hair fibre. In viewof their regulatory properties, in this study we investigated the interaction between hair follicledermal cells (DP and DS) and embryonic stem cells (ESCs), induced pluripotent stem cells(iPSCs) and haematopoietic stem cells. We found that co-culture of follicular dermal cells withESCs or iPSCs supported their prolonged maintenance in an apparently undifferentiated stateas established by differentiation assays, immunocytochemistry and RT-PCR for markers ofundifferentiated ESCs. We further showed that cytokines that are involved in ESC support arealso expressed by cultured follicle dermal cells, providing a possible explanation formaintenance of ES cell stemness in co-cultures. The same cytokines were expressed withinfollicles in situ in a pattern more consistent with a role in follicle growth activities than stem cellmaintenance. Finally we show that cultured mouse follicle dermal cells provide good stromalsupport for haematopoiesis in an established co-culture model. Human follicular dermal cellsrepresent an accessible and readily propagated source of feeder cells for pluripotent andhaematopoietic cells, and have potential for use in clinical applications.
Ghetti M, Topouzi H, Theocharidis G, et al., 2018, Sub-populations of dermal skin fibroblasts secrete distinct extracellular matrix: implications for using skin substitutes in the clinic, British Journal of Dermatology, Vol: 179, Pages: 381-393, ISSN: 1365-2133
BackgroundWhile several commercial dermoepidermal scaffolds can promote wound healing of the skin, the achievement of complete skin regeneration still represents a major challenge.ObjectivesTo perform biological characterization of self‐assembled extracellular matrices (ECMs) from three different subpopulations of fibroblasts found in human skin: papillary fibroblasts (Pfi), reticular fibroblasts (Rfi) and dermal papilla fibroblasts (DPfi).MethodsFibroblast subpopulations were cultured with ascorbic acid to promote cell‐assembled matrix production for 10 days. Subsequently, cells were removed and the remaining matrices characterized. Additionally, in another experiment, keratinocytes were seeded on the top of cell‐depleted ECMs to generate epidermal‐only skin constructs.ResultsWe found that the ECM self‐assembled by Pfi exhibited randomly oriented fibres associated with the highest interfibrillar space, reflecting ECM characteristics that are physiologically present within the papillary dermis. Mass spectrometry followed by validation with immunofluorescence analysis showed that thrombospondin 1 is preferentially expressed within the DPfi‐derived matrix. Moreover, we observed that epidermal constructs grown on DPfi or Pfi matrices exhibited normal basement membrane formation, whereas Rfi matrices were unable to support membrane formation.ConclusionsWe argue that inspiration can be taken from these different ECMs, to improve the design of therapeutic biomaterials in skin engineering applications.
Pantelireis N, Higgins C, 2018, A bald statement – current approaches to manipulate miniaturisation focus only on promoting hair growth, Experimental Dermatology, Vol: 27, Pages: 959-965, ISSN: 0906-6705
Hair plays a large part in communication and society with its role changing through time and across cultures. Most people don't leave the house before combing their hair or shaving their beard and for many hair loss or irregular hair growth can have a significant impact on their psychological health. Somewhat unsurprisingly, according to GMR Data today's global hair care industry is worth an estimated $87 Billion in 2018, with hair loss estimated at $2.8 Billion. Considering that no current hair loss related products can completely reverse hair loss, it is reasonable to believe this market could expand significantly with the discovery of a comprehensive therapy. As such, a great deal of research focuses on overcoming hair loss, and in particular, a common form of hair loss known as Androgenetic Alopecia (AGA) or male pattern baldness. In AGA hair follicles miniaturise in a large step change from a terminal to a vellus state. Within this viewpoint article, we discuss how influx and efflux of cells into and out from the dermal papilla can modulate dermal papilla size during the hair cycle. As dermal papilla size is positively correlated with the size of the hair fibre produced by a follicle, we argue here that therapies for treating AGA should be developed which can alter dermal papilla size, rather than just promote hair growth. We also discuss current therapeutics for AGA, and emphasize the importance of using the right model systems to analyse miniaturisation.
Kiani MT, Higgins CA, Almquist BD, 2018, The hair follicle: an underutilized source of cells and materials for regenerative medicine, ACS Biomaterials Science and Engineering, Vol: 4, Pages: 1193-1207, ISSN: 2373-9878
The hair follicle is one of only two structures within the adult body that selectively degenerates and regenerates, making it an intriguing organ to study and use for regenerative medicine. Hair follicles have been shown to influence wound healing, angiogenesis and neurogenesis, and harbor distinct populations of stem cells; this has led to cells from the follicle being used in clinical trials for tendinosis and chronic ulcers. In addition, keratin produced by the follicle in the form of a hair fiber provides an abundant source of biomaterials for regenerative medicine. In this review, we provide an overview of the structure of a hair follicle, explain the role of the follicle in regulating the microenvironment of skin and the impact on wound healing, explore individual cell types of interest for regenerative medicine, and cover several applications of keratin-based biomaterials.
Logan N, Arora H, Higgins C, 2017, Evaluating primary blast effects in vitro, Jove-Journal of Visualized Experiments, Vol: 127, ISSN: 1940-087X
Exposure to blast events can cause severe trauma to vital organs such as the lungs, ears, and brain. Understanding the mechanisms behind such blast-induced injuries is of great importance considering the recent trend towards the use of explosives in modern warfare and terrorist-related incidents. To fully understand blast-induced injury, we must first be able to replicate such blast events in a controlled environment using a reproducible method. In this technique using shock tube equipment, shock waves at a range of pressures can be propagated over live cells grown in 2D, and markers of cell viability can be immediately analyzed using a redox indicator assay and the fluorescent imaging of live and dead cells. This method demonstrated that increasing the peak blast overpressure to 127 kPa can stimulate a significant drop in cell viability when compared to untreated controls. Test samples are not limited to adherent cells, but can include cell suspensions, whole-body and tissue samples, through minor modifications to the shock tube setup. Replicating the exact conditions that tissues and cells experience when exposed to a genuine blast event is difficult. Techniques such as the one presented in this article can help to define damage thresholds and identify the transcriptional and epigenetic changes within cells that arise from shock wave exposure.
Topouzi H, Logan N, Williams G, et al., 2017, Methods for the isolation and 3D culture of dermal papilla cells from human hair follicles, Experimental Dermatology, Vol: 26, Pages: 491-496, ISSN: 1600-0625
The dermal papilla is a cluster of mesenchymal cells located at the base of the hair follicle which have a number of important roles in the regulation of hair growth. As a consequence, in vitro models of these cells are widely used to study the molecular mechanisms which underlie hair follicle induction, growth and maintenance. While dermal papilla from rodent hair follicles can be digested prior to cell isolation, the unique extracellular matrix composition found in human dermal papilla renders enzymes such as trypsin and collagenase insufficient for digestion of the dermal papilla into a single cell suspension. As such, to grow human dermal papilla cells in vitro, the papilla has to first be isolated via a micro-dissection approach from the follicle. In this article we describe the micro-dissection and culture methods, which we use within our laboratory, for the study of human dermal papilla cells.
Topouzi H, Higgins C, 2016, Changing faces: Can a new identity stop balding?, Experimental Dermatology, Vol: 25, Pages: 765-766, ISSN: 1600-0625
Higgins CA, Roger M, Hill R, et al., 2016, Multifaceted role of hair follicle dermal cells in bioengineered skins, British Journal of Dermatology, Vol: 176, Pages: 1259-1269, ISSN: 1365-2133
BACKGROUND: The method to generate bioengineered skin constructs was pioneered several decades ago, and nowadays these constructs are used regularly for the treatment of severe burns and non-healing wounds. Commonly, these constructs are comprised of skin fibroblasts within a collagen scaffold, forming the skin dermis, and stratified keratinocytes overlying this, forming the skin epidermis. In the past decade there has been a surge of interest in bioengineered skins, with researchers searching for alternative cell sources, or scaffolds, from which constructs can be established, and for more biomimetic equivalents with skin appendages. OBJECTIVES: In this manuscript we wanted to evaluate whether human hair follicle dermal cells can act as an alternative cell source for engineering the dermal component of engineered skin constructs. METHODS: We established in vitro skin constructs by incorporating into the collagenous dermal compartment either primary interfollicular dermal fibroblasts, hair follicle dermal papilla, or hair follicle dermal sheath cells. In vivo skins were established by mixing dermal cells and keratinocytes in chambers on top of immunologically compromised mice. RESULTS: All fibroblast subtypes were capable of supporting growth of overlying epithelial cells, both in vitro and in vivo. However, we found hair follicle dermal sheath cells to be superior to fibroblasts in their capacity to influence the establishment of a basal lamina. CONCLUSIONS: Human hair follicle dermal cells can be readily interchanged with interfollicular fibroblasts, and used as an alternative cell source for establishing the dermal component of engineered skin both in vitro and in vivo. This article is protected by copyright. All rights reserved.
Harel S, Higgins CA, Cerise JE, et al., 2015, Pharmacologic inhibition of JAK-STAT signaling promotes hair growth., Science Advances, Vol: 1, ISSN: 2375-2548
Several forms of hair loss in humans are characterized by the inability of hair follicles to enter the growth phase (anagen) of the hair cycle after being arrested in the resting phase (telogen). Current pharmacologic therapies have been largely unsuccessful in targeting pathways that can be selectively modulated to induce entry into anagen. We show that topical treatment of mouse and human skin with small-molecule inhibitors of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway results in rapid onset of anagen and subsequent hair growth. We show that JAK inhibition regulates the activation of key hair follicle populations such as the hair germ and improves the inductivity of cultured human dermal papilla cells by controlling a molecular signature enriched in intact, fully inductive dermal papillae. Our findings open new avenues for exploration of JAK-STAT inhibition for promotion of hair growth and highlight the role of this pathway in regulating the activation of hair follicle stem cells.
Topouzi H, Higgins CA, 2015, Expression map of three distinct skin fibroblast populations isolated from human skin, 45th Annual Meeting of the European-Society-for-Dermatological-Research, Publisher: NATURE PUBLISHING GROUP, Pages: S68-S68, ISSN: 0022-202X
Gledhill K, Guo Z, Umegaki-Arao N, et al., 2015, Melanin Transfer in Human 3D Skin Equivalents Generated Exclusively from Induced Pluripotent Stem Cells, PLOS ONE, Vol: 10, ISSN: 1932-6203
Higgins CA, 2014, Interrogating the integument: the role of the epidermis in hair induction, EXPERIMENTAL DERMATOLOGY, Vol: 23, Pages: 714-715, ISSN: 0906-6705
Xing L, Dai Z, Jabbari A, et al., 2014, Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition, Nature Medicine, Vol: 20, Pages: 1043-1049, ISSN: 1078-8956
Alopecia areata (AA) is a common autoimmune disease resulting from damage of the hair follicle by T cells. The immune pathways required for autoreactive T cell activation in AA are not defined limiting clinical development of rational targeted therapies1. Genome-wide association studies (GWAS)2 implicated ligands for the NKG2D receptor (product of the KLRK1 gene) in disease pathogenesis. Here, we show that cytotoxic CD8+NKG2D+ T cells are both necessary and sufficient for the induction of AA in mouse models of disease. Global transcriptional profiling of mouse and human AA skin revealed gene expression signatures indicative of cytotoxic T cell infiltration, an interferon-γ (IFN-γ) response and upregulation of several γ-chain (γc) cytokines known to promote the activation and survival of IFN-γ–producing CD8+NKG2D+ effector T cells. Therapeutically, antibody-mediated blockade of IFN-γ, interleukin-2 (IL-2) or interleukin-15 receptor β (IL-15Rβ) prevented disease development, reducing the accumulation of CD8+NKG2D+ T cells in the skin and the dermal IFN response in a mouse model of AA. Systemically administered pharmacological inhibitors of Janus kinase (JAK) family protein tyrosine kinases, downstream effectors of the IFN-γ and γc cytokine receptors, eliminated the IFN signature and prevented the development of AA, while topical administration promoted hair regrowth and reversed established disease. Notably, three patients treated with oral ruxolitinib, an inhibitor of JAK1 and JAK2, achieved near-complete hair regrowth within 5 months of treatment, suggesting the potential clinical utility of JAK inhibition in human AA.
Higgins CA, Petukhova L, Harel S, et al., 2014, FGF5 is a crucial regulator of hair length in humans, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 111, Pages: 10648-10653, ISSN: 0027-8424
Eungdamrong NJ, Higgins C, Guo Z, et al., 2014, Challenges and promises in modeling dermatologic disorders with bioengineered skin, Exp Biol Med (Maywood)
The tremendous cost of drug development is often attributed to the long time interval between identifying lead compounds in preclinical studies to assessing clinical efficacy in randomized clinical trials. Many candidate molecules show promise in cell culture or animal models, only to fail in late stage in human investigations. There is a need for novel technologies that allow investigators to quickly and reliably predict drug safety and efficacy. The advent of microtechnology has made it possible to integrate multiple microphysiologic organ systems into a single microfabricated chip. This review focuses on three-dimensional engineered skin, which has enjoyed a long history of uses both in clinical treatments of refractory ulcers and as a laboratory model. We discuss current biological and engineering challenges in construction of a robust bioengineered skin and provide a blueprint for its potential utility to model dermatologic disorders such as psoriasis or cutaneous drug reactions.
Furniss M, Higgins CA, Martinez-Mir A, et al., 2014, Identification of Distinct Mutations in AAGAB in Families with Type 1 Punctate Palmoplantar Keratoderma, JOURNAL OF INVESTIGATIVE DERMATOLOGY, Vol: 134, Pages: 1749-1752, ISSN: 0022-202X
Bhogal RK, Mouser PE, Higgins CA, et al., 2014, Protease activity, localization and inhibition in the human hair follicle, INTERNATIONAL JOURNAL OF COSMETIC SCIENCE, Vol: 36, Pages: 46-53, ISSN: 0142-5463
Higgins CA, Christiano AM, 2014, Regenerative medicine and hair loss: how hair follicle culture has advanced our understanding of treatment options for androgenetic alopecia, REGENERATIVE MEDICINE, Vol: 9, Pages: 101-111, ISSN: 1746-0751
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