Comparison of two human organoid models of lung and intestinal inflammation reveals Toll‐like receptor signalling activation and monocyte recruitment. Issue 5 (5th May 2020)

• Record Type: Journal Article
• Authors: Jose, Shyam Sushama; De Zuani, Marco; Tidu, Federico; Hortová Kohoutková, Marcela; Pazzagli, Lucia; Forte, Giancarlo; Spaccapelo, Roberta; Zelante, Teresa; Frič, Jan
• Is Part Of: Clinical & translational immunology. Volume 9:Issue 5(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-05-05
• Subjects: immune response -- infection -- leucocyte migration -- tissue organoids -- Toll‐like receptors; Immunologic diseases -- Periodicals; Immunology -- Periodicals; Clinical medicine -- Periodicals; Immune System Diseases -- therapy; Immunotherapy; Immunologic Factors -- therapeutic use; Translational Medical Research; Molecular Targeted Therapy; Clinical medicine; Immunologic diseases; Immunology; Periodicals; Periodicals; Fulltext; Internet Resources; Periodicals; 616.079
• DOI: 10.1002/cti2.1131
• Languages: English
• ISSNs: 2050-0068

Abstract

Abstract: 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. Abstract : We propose a novel tool to study the interactions between human mucosal tissues and infiltrating monocytes. Taking advantage of two models of human‐induced pluripotent stem cell‐derived lung and gut organoids, we compared their response to a panel of microbial ligands and their ability to host human primary monocytes. We show that both the organoids – even in the absence of tissue‐resident immune cells – successfully mimicked an immunocompetent environment able to respond to microbial insults and to promote the differentiation of patient‐derived immune cells.