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Long-Term and Clinically Relevant Full-Thickness Human Skin Equivalent for Psoriasis
ACS Applied Bio Materials ( IF 4.6 ) Pub Date : 2020-09-03 , DOI: 10.1021/acsabm.0c00202 Smriti Singh 1 , Yvonne Marquardt 2 , Rahul Rimal 1 , Akihiro Nishiguchi 1, 3 , Sebastian Huth 2 , Mitsuru Akashi 4 , Martin Moeller 1, 5 , Jens M Baron 2
ACS Applied Bio Materials ( IF 4.6 ) Pub Date : 2020-09-03 , DOI: 10.1021/acsabm.0c00202 Smriti Singh 1 , Yvonne Marquardt 2 , Rahul Rimal 1 , Akihiro Nishiguchi 1, 3 , Sebastian Huth 2 , Mitsuru Akashi 4 , Martin Moeller 1, 5 , Jens M Baron 2
Affiliation
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Psoriasis is an incurable, immune-mediated inflammatory disease characterized by the hyperproliferation and abnormal differentiation of keratinocytes. To study in depth the pathogenesis of this disease and possible therapy options suitable, pre-clinical models are required. Three-dimensional skin equivalents are a potential alternative to simplistic monolayer cultures and immunologically different animal models. However, current skin equivalents lack long-term stability, which jeopardizes the possibility to simulate the complex disease-specific phenotype followed by long-term therapeutic treatment. To overcome this limitation, the cell coating technique was used to fabricate full-thickness human skin equivalents (HSEs). This rapid and scaffold-free fabrication method relies on coating cell membranes with nanofilms using layer-by-layer assembly, thereby allowing extended cultivation of HSEs up to 49 days. The advantage in time is exploited to develop a model that not only forms a disease phenotype but can also be used to monitor the effects of topical or systemic treatment. To generate a psoriatic phenotype, the HSEs were stimulated with recombinant human interleukin 17A (rhIL-17A). This was followed by systemic treatment of the HSEs with the anti-IL-17A antibody secukinumab in the presence of rhIL-17A. Microarray and RT-PCR analysis demonstrated that HSEs treated with rhIL-17A showed downregulation of differentiation markers and upregulation of chemokines and cytokines, while treatment with anti-IL-17A antibody reverted these gene regulations. Gene ontology analysis revealed the proinflammatory and chemotactic effects of rhIL-17A on the established HSEs. These data demonstrated, at the molecular level, the effects of anti-IL-17A antibody on rhIL-17A-induced gene regulations. This shows the physiological relevance of the developed HSE and opens venues for its use as an alternative to ex vivo skin explants and animal testing.
中文翻译：
银屑病的长期和临床相关全层人体皮肤等效物
银屑病是一种无法治愈的免疫介导的炎症性疾病，其特征是角质形成细胞过度增殖和异常分化。为了深入研究这种疾病的发病机制和可能的合适治疗方案，需要临床前模型。三维皮肤等效物是简单的单层培养和免疫学不同的动物模型的潜在替代品。然而，目前的皮肤等效物缺乏长期稳定性，这会危及模拟复杂疾病特异性表型以及随后进行长期治疗的可能性。为了克服这一限制，细胞涂层技术被用于制造全层人体皮肤等效物 (HSE)。这种快速且无支架的制造方法依赖于使用逐层组装的纳米膜涂覆细胞膜，从而允许将 HSE 的培养时间延长至 49 天。利用时间优势开发一种模型，该模型不仅可以形成疾病表型，还可以用于监测局部或全身治疗的效果。为了产生银屑病表型，用重组人白细胞介素 17A (rhIL-17A) 刺激 HSE。随后在 rhIL-17A 存在下用抗 IL-17A 抗体苏金单抗对 HSE 进行全身治疗。微阵列和 RT-PCR 分析表明，用 rhIL-17A 处理的 HSE 显示出分化标志物的下调以及趋化因子和细胞因子的上调，而用抗 IL-17A 抗体处理则恢复了这些基因调控。基因本体分析揭示了 rhIL-17A 对已建立的 HSE 的促炎和趋化作用。这些数据表明，在分子水平上，抗IL-17A抗体对rhIL-17A诱导的基因调控的影响。这显示了已开发的 HSE 的生理相关性，并为其作为替代方案打开了场所。体外皮肤外植体和动物试验。
更新日期：2020-10-21
中文翻译：
银屑病的长期和临床相关全层人体皮肤等效物
银屑病是一种无法治愈的免疫介导的炎症性疾病，其特征是角质形成细胞过度增殖和异常分化。为了深入研究这种疾病的发病机制和可能的合适治疗方案，需要临床前模型。三维皮肤等效物是简单的单层培养和免疫学不同的动物模型的潜在替代品。然而，目前的皮肤等效物缺乏长期稳定性，这会危及模拟复杂疾病特异性表型以及随后进行长期治疗的可能性。为了克服这一限制，细胞涂层技术被用于制造全层人体皮肤等效物 (HSE)。这种快速且无支架的制造方法依赖于使用逐层组装的纳米膜涂覆细胞膜，从而允许将 HSE 的培养时间延长至 49 天。利用时间优势开发一种模型，该模型不仅可以形成疾病表型，还可以用于监测局部或全身治疗的效果。为了产生银屑病表型，用重组人白细胞介素 17A (rhIL-17A) 刺激 HSE。随后在 rhIL-17A 存在下用抗 IL-17A 抗体苏金单抗对 HSE 进行全身治疗。微阵列和 RT-PCR 分析表明，用 rhIL-17A 处理的 HSE 显示出分化标志物的下调以及趋化因子和细胞因子的上调，而用抗 IL-17A 抗体处理则恢复了这些基因调控。基因本体分析揭示了 rhIL-17A 对已建立的 HSE 的促炎和趋化作用。这些数据表明，在分子水平上，抗IL-17A抗体对rhIL-17A诱导的基因调控的影响。这显示了已开发的 HSE 的生理相关性，并为其作为替代方案打开了场所。体外皮肤外植体和动物试验。
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