On the relevance of an in vitro reconstructed human epidermis model for drug screening in atopic dermatitis

Hubaux, Roland; Bastin, Coralie; Salmon, Michel

doi:10.1111/exd.13810

Cited by 13 publications

(19 citation statements)

References 24 publications

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“…Cytokine cocktails usually contain IL-4 and IL-13 because these are two major Th2 cytokines found in the skin of AD patients, regardless of disease stage (nonlesional and acute/chronic lesional) [12]. Treatment of HSEs with IL-4 and IL-13 induced epidermal hyperplasia (acanthosis) and a reduction of FLG, which are two key cellular abnormalities associated with AD [103,104,105]. However, this treatment induced a thinning of the SC as well, which is opposite to the hyperkeratosis observed in AD [103,104].…”

Section: 3d Cultures Helped Unravel New Pathogenic Pathways In Atomentioning

confidence: 99%

“…Thus, these results show that alarmins affect the proliferation/differentiation process in lesional AD, potentially in an effort to restore the epidermis, but do not significantly trigger the release of other inflammatory mediators by KCs. HEEs treated with IL-4, IL-13, and an alarmin, namely IL-25, recapitulated epidermal features of lesional AD such as a widening of the intercellular spaces (spongiosis) and dysregulated expression of AD biomarkers, including a decrease in FLG, LOR, and E-cadherin at the protein and/or mRNA levels, along with an increase in carbonic anhydrase 2, neural epidermal growth factor L-Like protein 2 and hyaluronic acid synthase 3 [105]. These results also corroborate those from a previous study showing an imbalance of hyaluronan synthases 1 and 3 in AD lesions compared with healthy and non-lesional AD skin [108].…”

Section: 3d Cultures Helped Unravel New Pathogenic Pathways In Atomentioning

confidence: 99%

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3D-Organotypic Cultures to Unravel Molecular and Cellular Abnormalities in Atopic Dermatitis and Ichthyosis Vulgaris

Leman

Moosbrugger‐Martinz

Blunder

et al. 2019

Cells

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Atopic dermatitis (AD) is characterized by dry and itchy skin evolving into disseminated skin lesions. AD is believed to result from a primary acquired or a genetically-induced epidermal barrier defect leading to immune hyper-responsiveness. Filaggrin (FLG) is a protein found in the cornified envelope of fully differentiated keratinocytes, referred to as corneocytes. Although FLG null mutations are strongly associated with AD, they are not sufficient to induce the disease. Moreover, most patients with ichthyosis vulgaris (IV), a monogenetic skin disease characterized by FLG homozygous, heterozygous, or compound heterozygous null mutations, display non-inflamed dry and scaly skin. Thus, all causes of epidermal barrier impairment in AD have not yet been identified, including those leading to the Th2-predominant inflammation observed in AD. Three dimensional organotypic cultures have emerged as valuable tools in skin research, replacing animal experimentation in many cases and precluding the need for repeated patient biopsies. Here, we review the results on IV and AD obtained with epidermal or skin equivalents and consider these findings in the context of human in vivo data. Further research utilizing complex models including immune cells and cutaneous innervation will enable finer dissection of the pathogenesis of AD and deepen our knowledge of epidermal biology.

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Section: 3d Cultures Helped Unravel New Pathogenic Pathways In Atomentioning

confidence: 99%

Section: 3d Cultures Helped Unravel New Pathogenic Pathways In Atomentioning

confidence: 99%

3D-Organotypic Cultures to Unravel Molecular and Cellular Abnormalities in Atopic Dermatitis and Ichthyosis Vulgaris

Leman

Moosbrugger‐Martinz

Blunder

et al. 2019

Cells

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“…Experiments targeting the activation of repair SCs and probing SC signalling pathways could be accomplished with ex vivo and in vitro human skin models that are cultured with human neurons differentiated from induced pluripotent stem cells. [ ] The Crispr/Cas9 system could also be used to selective target SC genes in these in vitro and ex vivo models. This question can also be tested in appropriate mouse models.…”

Section: Discussionmentioning

confidence: 99%

Schwann cells as underestimated, major players in human skin physiology and pathology

Bray

Chéret

Yosipovitch

et al. 2019

Experimental Dermatology

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Schwann cells (SCs) have long been recognized for their ability to support repair and promote axon regeneration following injury to the peripheral nervous system. In response to nerve injury, they rapidly dedifferentiate into a precursor‐like state, secrete an array of inflammatory mediators and growth factors, proliferate, undergo epithelial‐to‐mesenchymal‐like transformation to facilitate migration, phagocytose cellular debris and remodel the extracellular environment to promote regeneration of axons through the site of injury. However, even though a cutaneous role for SCs is becoming increasingly recognized, we argue in this Viewpoint essay that the likely complex functions of SCs in skin physiology and pathology beyond skin sensation and nerve repair deserve more attention and systemic research than they have received so far. For example, SCs promote wound healing, disseminate infection in leprosy, support the growth of neurofibromas/schwannomas and facilitate/accelerate the growth and invasion of melanoma. Despite representing a major dermal cell population, comparatively little is still known about the role of SCs in other dermatoses. To quintessentially illustrate the opportunities that promise to arise from a new skin research focus on SCs, we focus on two dermatoses that are not traditionally associated with SCs, that is, psoriasis and atopic dermatitis (AD), since both show distinct SC changes along with continuous nerve fibre degeneration and regeneration, and an impact of denervation on skin lesions. Specifically, we critically discuss the hypothesis that repeated activation of the SC repair programme occurs in and contributes to psoriasis and AD and delineate experimental approaches how to probe this clinically relevant hypothesis.

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“…Therefore, there is a great need for human systems to study human diseases. Three-dimensional skin organoid models are emerging tools implemented in many aspects of skin research such as the study of barrier properties (El Ghalbzouri et al, 2008;Danso et al, 2015), wound healing (El Ghalbzouri et al, 2004;Egles et al, 2010;van Kilsdonk et al, 2013), bacterial infection, biofilm formation, and screening of antimicrobial peptides (Holland et al, 2009;Shepherd et al, 2009;de Breij et al, 2012de Breij et al, , 2018Boekema et al, 2013;Haisma et al, 2013Haisma et al, , 2014Haisma et al, , 2016van Drongelen et al, 2014;den Reijer et al, 2016), and inflammatory cutaneous diseases (van den Bogaard et al, 2014;Honzke et al, 2016;Hubaux et al, 2018).…”

Section: Skin Organoidsmentioning

confidence: 99%

Utilizing Organoid and Air-Liquid Interface Models as a Screening Method in the Development of New Host Defense Peptides

Choi

Lee

et al. 2020

Front. Cell. Infect. Microbiol.

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Host defense peptides (HDPs), also known as antimicrobial peptides, are naturally occurring polypeptides (∼12-50 residues) composed of cationic and hydrophobic amino acids that adopt an amphipathic conformation upon folding usually after contact with membranes. HDPs have a variety of biological activities including immunomodulatory, anti-inflammatory, anti-bacterial, and anti-biofilm functions. Although HDPs have the potential to address the global threat of antibiotic resistance and to treat immune and inflammatory disorders, they have yet to achieve this promise. Indeed, there are several challenges associated with bringing peptide-based drug candidates from the lab bench to clinical practice, including identifying appropriate indications, stability, toxicity, and cost. These challenges can be addressed in part by the development of innate defense regulator (IDR) peptides and peptidomimetics, which are synthetic derivatives of HDPs with similar or better efficacy, increased stability, and reduced toxicity and cost of the original HDP. However, one of the largest gaps between basic research and clinical application is the validity and translatability of conventional model systems, such as cell lines and animal models, for screening HDPs and their derivatives as potential drug therapies. Indeed, such translation has often relied on animal models, which have only limited validity. Here we discuss the recent development of human organoids for disease modeling and drug screening, assisted by the use of omics analyses. Organoids, developed from primary cells, cell lines, or human pluripotent stem cells, are three-dimensional, self-organizing structures that closely resemble their corresponding in vivo organs with regards to immune responses, tissue organization, and physiological properties; thus, organoids represent a reliable method for studying efficacy, formulation, toxicity and to some extent drug stability and pharmacodynamics. The use of patient-derived organoids enables the study of patient-specific efficacy, toxicogenomics and drug response predictions. We outline how organoids and omics data analysis can be leveraged to aid in the clinical translation of IDR peptides.

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On the relevance of an in vitro reconstructed human epidermis model for drug screening in atopic dermatitis

Cited by 13 publications

References 24 publications

3D-Organotypic Cultures to Unravel Molecular and Cellular Abnormalities in Atopic Dermatitis and Ichthyosis Vulgaris

3D-Organotypic Cultures to Unravel Molecular and Cellular Abnormalities in Atopic Dermatitis and Ichthyosis Vulgaris

Schwann cells as underestimated, major players in human skin physiology and pathology

Utilizing Organoid and Air-Liquid Interface Models as a Screening Method in the Development of New Host Defense Peptides

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