31 results found
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
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.
Boyle C, Plotczyk M, Fayos Villalta S, et al., Morphology and composition play distinct and complementary roles in the tolerance of plantar skin to mechanical load, Science Advances, ISSN: 2375-2548
Plantar skin on the soles of the feet has a distinct morphology and composition that is thought to enhance its tolerance ofmechanical loads, although the individual contributions of morphology and compositionhave never been quantified. Here, we combine multi-scale mechanical testing and computational models of load bearing to quantify the mechanical environment of both plantar and non-plantar skinunder load. We find that morphology and composition play distinct and complementary roles in plantar skin’ load tolerance. More specifically, the thick stratum corneum provides protection from stress-based injuriessuch as skin tears and blisters,while epidermal and dermal composition provide protection from deformation-based injuriessuch 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 etiologyof skin injury.
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
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
Guo Z, Higgins CA, Gillette BM, et al., 2013, Building a microphysiological skin model from induced pluripotent stem cells, STEM CELL RESEARCH & THERAPY, Vol: 4
Higgins CA, Chen JC, Cerise JE, et al., 2013, Microenvironmental reprogramming by three-dimensional culture enables dermal papilla cells to induce de novo human hair-follicle growth, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 19679-19688, ISSN: 0027-8424
Itoh M, Umegaki-Arao N, Guo Z, et al., 2013, Generation of 3D Skin Equivalents Fully Reconstituted from Human Induced Pluripotent Stem Cells (iPSCs), PLOS ONE, Vol: 8, ISSN: 1932-6203
Hill RP, Gledhill K, Gardner A, et al., 2012, Generation and Characterization of Multipotent Stem Cells from Established Dermal Cultures, PLOS ONE, Vol: 7, ISSN: 1932-6203
Higgins CA, Itoh M, Inoue K, et al., 2012, Reprogramming of Human Hair Follicle Dermal Papilla Cells into Induced Pluripotent Stem Cells, JOURNAL OF INVESTIGATIVE DERMATOLOGY, Vol: 132, Pages: 1725-1727, ISSN: 0022-202X
De Berker D, Higgins CA, Jahoda C, et al., 2012, Biology of Hair and Nails, Dermatology, 3rd Edition, Editors: Bolognia, Jorizzo, Schaffer, Publisher: Elsevier Publishing, ISBN: 9780723435716
Better comprehend the clinical-pathological relationship of skin disease with increased histologic coverage. Bolognia's Dermatology is the ultimate multimedia reference for residents in training AND the experienced practitioner.
Higgins CA, Westgate GE, Jahoda CAB, 2011, Modulation in Proteolytic Activity Is Identified as a Hallmark of Exogen by Transcriptional Profiling of Hair Follicles, JOURNAL OF INVESTIGATIVE DERMATOLOGY, Vol: 131, Pages: 2349-2357, ISSN: 0022-202X
Higgins CA, Richardson GD, Ferdinando D, et al., 2010, Modelling the hair follicle dermal papilla using spheroid cell cultures, EXPERIMENTAL DERMATOLOGY, Vol: 19, Pages: 546-548, ISSN: 0906-6705
Higgins CA, Richardson GD, Westgate GE, et al., 2009, Exogen involves gradual release of the hair club fibre in the vibrissa follicle model, EXPERIMENTAL DERMATOLOGY, Vol: 18, Pages: 793-795, ISSN: 0906-6705
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