Abstract
A common bottleneck in any drug development process is finding sufficiently accurate models that capture key aspects of disease development and progression. Conventional drug screening models often rely on simple 2D culture systems that fail to recapitulate the complexity of the organ situation. In this study, we show the application of a robust high throughput 3D gut-on-a-chip model for investigating hallmarks of inflammatory bowel disease (IBD). Using the OrganoPlate platform, we subjected enterocyte-like cells to an immune-relevant inflammatory trigger in order to recapitulate key events of IBD and to further investigate the suitability of this model for compound discovery and target validation activities. The induction of inflammatory conditions caused a loss of barrier function of the intestinal epithelium and its activation by increased cytokine production, two events observed in IBD physiopathology. More importantly, anti-inflammatory compound exposure prevented the loss of barrier function and the increased cytokine release. Furthermore, knockdown of key inflammatory regulators RELA and MYD88 through on-chip adenoviral shRNA transduction alleviated IBD phenotype by decreasing cytokine production. In summary, we demonstrate the routine use of a gut-on-a-chip platform for disease-specific aspects modeling. The approach can be used for larger scale disease modeling, target validation and drug discovery purposes.
Highlights
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a complex chronic idiopathic disease severely incapacitating the life of more than 2.5 to 3 million Europeans, bringing a high socio-economic burden to society [1,2,3]
Our results show that this 3D model can be used as an in vitro tool for drug development in an accelerated manner and opens the way to more pfohrydsiroulgogdiecavlellyopremleevnatnitnmanodaeclcseulesraabtleedinmhanignhertharnodugohppenust ethxepewriamyetnotms. ore physiologically relevant models usable in high throughput experiments
The Organ-on-a-Chip technology offers a valid alternative that promises increased throughput while achieving higher physiological relevance when compared to current traditional membrane inserts such as Transwells
Summary
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a complex chronic idiopathic disease severely incapacitating the life of more than 2.5 to 3 million Europeans, bringing a high socio-economic burden to society [1,2,3]. Standard in vitro setups usually include the static culture of epithelial cells on rigid membranes separating two different chambers, sometimes comprising an immune component [18] Such conventional membrane insert-based systems, often called 2.5D or Transwell systems, are a useful tool with medium throughput but do not recapitulate 3D cell organization, which has proven to be important for increased physiological relevance [19]. There are some shortcomings associated with such silicon rubber chips including the lack of scalability and the reduction of bioavailability of some drugs and small molecules due to unspecific adsorption [24,25] To overcome these limitations and to allow the integration of Organ-on-a-Chip in the drug development process, we further adapted a recently published gut-on-a-chip system [26] to mimic inflammatory conditions. WWee sshhooww tthhaatt tthheeTTEEEERRvvaalluueessooffCCaaccoo--22ttuubbuulleessccoonnttiinnuuoouussllyy iinnccrreeaassee aanndd ssttaabbiilliissee aafftteerr 44 ddaayyss ooff ccuullttuurree uunnttiill tthhee eenndd ooff tthhee eexxppeerriimmeennttaattiioonn ((FFiigguurree 11EE))
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