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Comparison of two human organoid models of lung and intestinal inflammation reveals Toll-like receptor signalling activation and monocyte recruitment.
Clinical & Translational Immunology ( IF 5.8 ) Pub Date : 2020-05-05 , DOI: 10.1002/cti2.1131
Shyam Sushama Jose 1 , Marco De Zuani 1 , Federico Tidu 1, 2 , Marcela Hortová Kohoutková 1 , Lucia Pazzagli 3 , Giancarlo Forte 1 , Roberta Spaccapelo 3 , Teresa Zelante 3 , Jan Frič 1, 4
Affiliation  

Objectives The activation of immune responses in mucosal tissues is a key factor for the development and sustainment of several pathologies including infectious diseases and autoimmune diseases. However, translational research and personalised medicine struggle to advance because of the lack of suitable preclinical models that successfully mimic the complexity of human tissues without relying on in vivo mouse models. Here, we propose two in vitro human 3D tissue models, deprived of any resident leucocytes, to model mucosal tissue inflammatory processes. Methods We developed human 3D lung and intestinal organoids differentiated from induced pluripotent stem cells to model mucosal tissues. We then compared their response to a panel of microbial ligands and investigated their ability to attract and host human primary monocytes. Results Mature lung and intestinal organoids comprised epithelial (EpCAM+) and mesenchymal (CD73+) cells which responded to Toll-like receptor stimulation by releasing pro-inflammatory cytokines and expressing tissue inflammatory markers including MMP9, COX2 and CRP. When added to the organoid culture, primary human monocytes migrated towards the organoids and began to differentiate to an 'intermediate-like' phenotype characterised by increased levels of CD14 and CD16. Conclusion We show that human mucosal organoids exhibit proper immune functions and successfully mimic an immunocompetent tissue microenvironment able to host patient-derived immune cells. Our experimental set-up provides a novel tool to tackle the complexity of immune responses in mucosal tissues which can be tailored to different human pathologies.

中文翻译:

比较两种肺部和肠道炎症的类器官模型揭示了 Toll 样受体信号激活和单核细胞募集。

目的 黏膜组织中免疫反应的激活是包括感染性疾病和自身免疫性疾病在内的多种病理学发展和维持的关键因素。然而,由于缺乏合适的临床前模型来成功模拟人体组织的复杂性,而不依赖于体内小鼠模型,转化研究和个性化医学难以取得进展。在这里,我们提出了两个体外人类 3D 组织模型,没有任何常驻白细胞,以模拟粘膜组织炎症过程。方法 我们开发了从诱导多能干细胞分化而来的人类 3D 肺和肠类器官来模拟粘膜组织。然后,我们比较了它们对一组微生物配体的反应,并研究了它们吸引和宿主人类原代单核细胞的能力。结果 成熟的肺和肠道类器官包括上皮 (EpCAM+) 和间充质 (CD73+) 细胞,它们通过释放促炎细胞因子和表达包括 MMP9、COX2 和 CRP 在内的组织炎症标志物来响应 Toll 样受体刺激。当添加到类器官培养物中时,原代人类单核细胞向类器官迁移并开始分化为以 CD14 和 CD16 水平升高为特征的“中间样”表型。结论 我们表明,人类黏膜类器官表现出适当的免疫功能,并成功地模拟了能够容纳患者衍生免疫细胞的免疫活性组织微环境。我们的实验装置提供了一种新工具来解决粘膜组织中免疫反应的复杂性,可以针对不同的人类病理进行定制。
更新日期:2020-05-05
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