Development of a human primary gut-on-a-chip to model inflammatory processes

Beaurivage, Claudia; Kanapeckaitė, Austė; Loomans, Cindy J.M.; Erdmann, Kai S.; Stallen, Jan; Janssen, Richard A. J.

doi:10.1038/s41598-020-78359-2

Cited by 106 publications

(84 citation statements)

References 69 publications

(108 reference statements)

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“…A significant need in this regard, and what poses an important limitation to our knowledge, is the challenge of obtaining direct access to relevant tissues such as the intestine and the enthesis structures. Use of newer in vitro systems like organ-on-a-chip and intestinal organoids derived from human subjects has the potential to allow mechanistic studies including microbe-host interactions [92][93][94][95] without having to use murine models.…”

Section: Spondyloarthritis Spondyloarthritis Spondyloarthritismentioning

confidence: 99%

The arthritis connection to inflammatory bowel disease (IBD): why has it taken so long to understand it?

2021

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Inflammatory bowel disease (IBD) associated arthritis is a subgroup of spondyloarthritis (SpA) that has suffered from lack of recognition in rheumatology clinical and research circles for over 100 years. Although clinically distinguishable from rheumatoid arthritis and ankylosing spondylitis, it took advances in detection systems in the middle of the last century (rheumatoid factor, HLA-B27) to convincingly make the final separations. We now know that significant numbers of patients with SpA have associated clinical IBD and almost half of them show subclinical gut inflammation, yet the connection between the gut and the musculoskeletal system has remained a vexing problem. Two publications from Nathan Zvaifler (one in 1960, the other in 1975) presciently described the relationship between the gut and the spine/peripheral joints heralding much of the work present today in laboratories around the world trying to examine basic mechanisms for the connections (there are likely to be many) between the gut, the environment (presumably our intestinal flora) and the downstream effect on the musculoskeletal system. The role of dysregulated microbiome along with microbiome-driven T helper 17 cell expansion and immune cell migration to the joints has been recognised, all of which occur in the appropriate context of genetic background inside and outside of the human leucocyte antigen system. Moreover, different adhesion molecules that mediate immune cells homing to the gut and joints have been noted. In this review, we studied the origins and evolution of IBD-arthritis, proposed pathogenic mechanisms and the current gaps that need to be filled for a complete understanding of IBD-arthritis.

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Section: Spondyloarthritis Spondyloarthritis Spondyloarthritismentioning

confidence: 99%

The arthritis connection to inflammatory bowel disease (IBD): why has it taken so long to understand it?

2021

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“…Other groups have successfully co-cultured 3-D gastrointestinal organoids with intraepithelial lymphocytes ( Nozaki et al, 2016 ), T cells ( Dijkstra et al, 2018 ), and both DCs and cytotoxic T cells ( Chakrabarti et al, 2018 ). Sophisticated microphysiological systems (MPSs) that integrate gastrointestinal epithelial cell monolayers and immune components also have been established by multiple groups ( Kim and Ingber, 2013 ; Kim et al, 2016 ; Shin and Kim, 2018 ; Beaurivage et al, 2020 ). However, monolayer systems frequently lack critical features of 3-D spherical organoids, such as oxygen gradients, crypt and gland formation and physiological tissue patterning ( Williamson et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

A Synthetic Hydrogel, VitroGel® ORGANOID-3, Improves Immune Cell-Epithelial Interactions in a Tissue Chip Co-Culture Model of Human Gastric Organoids and Dendritic Cells

et al. 2021

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Immunosurveillance of the gastrointestinal epithelium by mononuclear phagocytes (MNPs) is essential for maintaining gut health. However, studying the complex interplay between the human gastrointestinal epithelium and MNPs such as dendritic cells (DCs) is difficult, since traditional cell culture systems lack complexity, and animal models may not adequately represent human tissues. Microphysiological systems, or tissue chips, are an attractive alternative for these investigations, because they model functional features of specific tissues or organs using microscale culture platforms that recreate physiological tissue microenvironments. However, successful integration of multiple of tissue types on a tissue chip platform to reproduce physiological cell-cell interactions remains a challenge. We previously developed a tissue chip system, the gut organoid flow chip (GOFlowChip), for long term culture of 3-D pluripotent stem cell-derived human intestinal organoids. Here, we optimized the GOFlowChip platform to build a complex microphysiological immune-cell-epithelial cell co-culture model in order to study DC-epithelial interactions in human stomach. We first tested different tubing materials and chip configurations to optimize DC loading onto the GOFlowChip and demonstrated that DC culture on the GOFlowChip for up to 20 h did not impact DC activation status or viability. However, Transwell chemotaxis assays and live confocal imaging revealed that Matrigel, the extracellular matrix (ECM) material commonly used for organoid culture, prevented DC migration towards the organoids and the establishment of direct MNP-epithelial contacts. Therefore, we next evaluated DC chemotaxis through alternative ECM materials including Matrigel-collagen mixtures and synthetic hydrogels. A polysaccharide-based synthetic hydrogel, VitroGel®-ORGANOID-3 (V-ORG-3), enabled significantly increased DC chemotaxis through the matrix, supported organoid survival and growth, and did not significantly alter DC activation or viability. On the GOFlowChip, DCs that were flowed into the chip migrated rapidly through the V-ORG matrix and reached organoids embedded deep within the chip, with increased interactions between DCs and gastric organoids. The successful integration of DCs and V-ORG-3 embedded gastric organoids into the GOFlowChip platform now permits real-time imaging of MNP-epithelial interactions and other investigations of the complex interplay between gastrointestinal MNPs and epithelial cells in their response to pathogens, candidate drugs and mucosal vaccines.

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“…In addition, a pIOAC incorporating intestinal epithelial cells derived from human intestinal organoids and monocyte-derived macrophages has been successfully fabricated to simulate key aspects of the intestine of individuals with IBD. Intriguingly, the inflammatory trigger-induced gene expression profile in this model was similar to those in patients with IBD, opening the doors to personalized medicine [ 152 ]. Recently, studies with human intestinal organoids have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) preferentially infects mature enterocytes over enteroendocrine and goblet cells [ 153 ].…”

Section: Future Perspectives In Personalized Medicinementioning

confidence: 99%

Intestinal Models for Personalized Medicine: from Conventional Models to Microfluidic Primary Intestine-on-a-chip

Chen

Zhao

et al. 2021

Stem Cell Rev and Rep

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Intestinal dysfunction is frequently driven by abnormalities of specific genes, microbiota, or microenvironmental factors, which usually differ across individuals, as do intestinal physiology and pathology. Therefore, it’s necessary to develop personalized therapeutic strategies, which are currently limited by the lack of a simulated intestine model. The mature human intestinal mucosa is covered by a single layer of columnar epithelial cells that are derived from intestinal stem cells (ISCs). The complexity of the organ dramatically increases the difficulty of faithfully mimicking in vivo microenvironments. However, a simulated intestine model will serve as an indispensable foundation for personalized drug screening. In this article, we review the advantages and disadvantages of conventional 2-dimensional models, intestinal organoid models, and current microfluidic intestine-on-a-chip (IOAC) models. The main technological strategies are summarized, and an advanced microfluidic primary IOAC model is proposed for personalized intestinal medicine. In this model, primary ISCs and the microbiome are isolated from individuals and co-cultured in a multi-channel microfluidic chip to establish a microengineered intestine device. The device can faithfully simulate in vivo fluidic flow, peristalsis-like motions, host-microbe crosstalk, and multi-cell type interactions. Moreover, the ISCs can be genetically edited before seeding, and monitoring sensors and post-analysis abilities can also be incorporated into the device to achieve high-throughput and rapid pharmaceutical studies. We also discuss the potential future applications and challenges of the microfluidic platform. The development of cell biology, biomaterials, and tissue engineering will drive the advancement of the simulated intestine, making a significant contribution to personalized medicine in the future. Graphical abstract The intestine is a primary organ for digestion, absorption, and metabolism, as well as a major site for the host-commensal microbiota interaction and mucosal immunity. The complexity of the organ dramatically increases the difficulty of faithfully mimicking in vivo microenvironments, though physiological 3-dimensional of the native small intestinal epithelial tissue has been well documented. An intestinal stem cells-based microfluidic intestine-on-a-chip model that faithfully simulate in vivo fluidic flow, peristalsis-like motions, host-microbe crosstalk, and multi-cell type interactions will make a significant contribution.

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Development of a human primary gut-on-a-chip to model inflammatory processes

Cited by 106 publications

References 69 publications

The arthritis connection to inflammatory bowel disease (IBD): why has it taken so long to understand it?

The arthritis connection to inflammatory bowel disease (IBD): why has it taken so long to understand it?

A Synthetic Hydrogel, VitroGel® ORGANOID-3, Improves Immune Cell-Epithelial Interactions in a Tissue Chip Co-Culture Model of Human Gastric Organoids and Dendritic Cells

Intestinal Models for Personalized Medicine: from Conventional Models to Microfluidic Primary Intestine-on-a-chip

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