Neutrophilic infiltration in organ-on-a-chip model of tissue inflammation
Neutrophilic infiltration in organ-on-a-chip model of tissue inflammation
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DOI：
10.1039/d0lc00417k
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发表时间：
2020-09-21
期刊：
影响因子：
6.1
通讯作者：
Moisan, Annie
中科院分区：
文献类型：
--
作者：
Gjorevski, Nikolce;Avignon, Blandine;Moisan, Annie
组织炎症的多相病因学和物种之间的基本免疫学差异使得炎症病理学难以在动物模型中重现，并且解释了从啮齿类动物成功转化为人类的治疗方法的缺乏。在这里，我们提出了一个用于实验性炎症疾病的人类相关芯片器官平台。我们通过将肠上皮细胞和免疫细胞整合到微流体室中来创建免疫活性体外肠模型，微流体室允许细胞穿过细胞外基质（ECM）和流体通道移动。这是第一个集成粘膜屏障、三维 ECM、驻留和浸润免疫细胞的模型，并模拟最终触发代表炎症的细胞过程的功能串扰。在稳态条件下，肠上皮细胞形成紧密的上皮，上皮下巨噬细胞未激活。促炎介质的引入会触发巨噬细胞活化和炎症引起的肠道屏障渗漏。平行的、基质分离的非上皮通道中的中性粒细胞被这种促炎微环境吸引，并通过细胞外基质迁移，进一步加剧组织炎症和损伤。通过该模型，我们为在受控的人体相关系统中概括和研究组织炎症的发生提供了基础。
The multiphasic etiology of tissue inflammation and the fundamental immunological differences between species render inflammatory pathologies difficult to recapitulate in animal models, and account for the paucity of therapies that are successfully translated from rodents to humans. Here, we present a human-relevant organ-on-a-chip platform for experimental inflammatory diseases. We created an immunocompetentin vitrogut model by incorporating intestinal epithelial and immune cells into microfluidic chambers that permit cell movement across an extracellular matrix (ECM) and fluidic channels. This is the first model that integrates a mucosal barrier, a three-dimensional ECM, resident and infiltrating immune cells, and simulates a functional crosstalk that ultimately triggers cellular processes representative of inflammation. Under homeostatic conditions, enterocytes form a tight epithelium and subepithelial macrophages are non-activated. Introduction of pro-inflammatory mediators triggers macrophage activation and inflammation-induced intestinal barrier leakiness. Neutrophils in a parallel, matrix-separated non-epithelial channel are attracted by such a pro-inflammatory microenvironment and migrate through the extracellular matrix, further exacerbating tissue inflammation and damage. With this model, we provide the foundations to recapitulate and investigate the onset of tissue inflammation in a controlled, human-relevant system.