Abstract
ObjectivesThe 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.MethodsWe 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.ResultsMature 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.ConclusionWe 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.
Highlights
Mucosal tissues, especially the lungs and gut, provide a large surface area for host–microbe interaction and act as the primary defence against potential pathogens by providing a physical barrier, secreting immune molecules and mediating specific cellular immunity
Mucosal tissue interfaces play a key role in the maintenance of organismal homeostasis by mediating communication between the external space and the cells, while regulating microbiota sampling
Since pathogen recognition receptor (PRR) play a key role during infection, we aimed to describe their presence and activity in our 3D systems
Summary
Especially the lungs and gut, provide a large surface area for host–microbe interaction and act as the primary defence against potential pathogens by providing a physical barrier, secreting immune molecules and mediating specific cellular immunity. Orchestrated interactions of innate and adaptive immune cells[1] with the cells forming the mucosal tissue result in the release of cytokines, chemokines and other molecules – such as mucus and defensins, important for the maintenance of tissue homeostasis.[2,3]. The epithelial fraction of mucosal tissues acts as the primary source of cytokines mediating the recruitment of immune cells both under steadystate conditions and during infection.[4,5]. Due to the cytokine milieu secreted by mucosal tissues, they are host to multiple tissue-resident immune cell subsets.[6]. The intense recruitment of immune cells – including neutrophils and monocytes – increases the cellular complexity of these anatomical districts.[7,8]. The exact mechanisms underlying the complex immune response of the mucosal microenvironment remain controversial
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