Breaking New Ground in IBD Research with Organ-Chips

Emulate’s new immune cell recruitment application for the Emulate Colon Intestine- Chip (1, 2) demonstrates the power of being able to explore complex immune responses with unprecedented physiological relevance. Chris Carman, Emulate Director of Immunology, tells us more.

What is immune cell recruitment?
 

Our immune system monitors for signs of danger, damage, and infection. Immune cells travel through the bloodstream until they are recruited to enter infected tissue, where they respond to the infection, clear it, heal the tissue, and then either die or return to the bloodstream. It is very important that this process is tightly regulated and self- limited; if it weren’t, we’d suffer from all kinds of autoimmune diseases starting at a very early age. So, for the immune system to function properly and to maintain health and homeostasis, the selectivity of immune cell recruitment and response is essential.

Why is immune cell recruitment important when researching a disease like inflammatory bowel disease (IBD)? For the vast majority of us, the immune system functions as it should, with immune cells traveling to a particular location with a specific purpose. When their job is complete, the immune cells clear out and the inflammation subsides. But for those

afflicted with inflammatory bowel disease (IBD), the process becomes dysregulated and immune cells are excessively recruited to unintended locations. And that results in further dysregulated immune cell recruitment and reactions, triggering a vicious cycle of pro-inflammatory responses that ultimately cause tissue damage and dysfunction, leading to disease.

Dysregulated, excessive inflammation is at the heart of most major human diseases. IBD is an excellent example of a disease that depends on – and is ultimately driven by – excessive, dysregulated immune reactions.

How is Emulate’s work helping to unravel immune cell recruitment and IBD?
 

IBD is a complex, chronic disease that is incredibly difficult to study. Its hallmark – the disruption of the epithelial barrier – causes materials inside the intestine, including bacteria, to leak, which then kicks off a subsequent escalation and vicious cycle of inflammation.

At Emulate, we have modeled the entire process – something that is unprecedented. As inflammation begins, there is always a priming cue that causes local tissue to undergo changes, including critical pro-inflammatory reprogramming of endothelial cells lining the blood vessels. Our model begins precisely at this priming step, and then goes on to capture the full course of disease progression.

To develop this application, we used the Colon Intestine-Chip – a primary human cell model of the colonic barrier that co- cultures organoid-derived epithelium with colon-specific vasculature. We demonstrate in published work that the morphology, function, and transcriptome signature of this model very closely recapitulates human physiology in a manner that is dependent upon the cell- cell interactions with vascular endothelial cells (3). This feature is unique to this model; competing technologies, such as organoid-based approaches, lack vasculature.

To initiate inflammation, we applied a well- established cytokine – a priming stimulus for driving early IBD progression. Critically, we next introduced immune cells – specifically, peripheral blood mononuclear cells into the Colon Intestine- Chip’s vascular channel. With this step, our model was able to capture the complexity of human pathophysiology and mimic most of the critical sequence of events for IBD, including immune cell adhesion to the endothelium and migration into the tissue, activation of complex interstitial immune signalling networks, and finally a release of the critical hallmark cytokines and disruption of the epithelial barrier.

How will this model benefit IBD research?
 

First, and crucially, the Colon Intestine- Chip represents a more complete and complex model of both human intestinal physiology and disease; we believe that this unprecedented completeness – coupled with experimental tractability – will lead to a deeper mechanistic understanding of IBD. Second, and equally as important, we believe this model will enable researchers to identify new therapeutic IBD targets more precisely, so that better and more effective therapeutics can be developed and validated. Ultimately, we hope our model will help researchers greatly diminish the attrition rate of drugs moving into the clinic.

How do traditional models of IBD compare with Emulate’s Organ-Chip model?
 

Traditional models used to study IBD and develop therapeutics for the disease have yielded significant knowledge, but they also exhibit important limitations. For example, conventional in vivo studies are almost always performed in mice, which suffer from species-specific differences – a factor that is particularly important when studying the immune system. At the same time, traditional in vitro models (whether epithelial cell lines or organoid cultures) are highly constrained by their limited complexity. Each of these models has strengths and weaknesses, but they are really only able to look at one piece of the puzzle, and none capture the full complexity of human disease. As such, researchers can only capture a subset of therapeutic targets with these models. Because the Colon Intestine-Chip and immune cell recruitment application capture a more complete sequence of events for IBD, researchers can study a much broader spectrum of disease targets and, subsequently, develop more effective therapeutics.

Beyond the immune cell recruitment application, how else can Organ-on-Chip technology be used for immunology?
 

In addition to modeling circulating immune cell recruitment, researchers can incorporate so-called resident immune cells – which also play essential roles in driving immune response – into organ- Chip models. A couple of our developed models apply this functionality today; for example, the Liver-Chip incorporates Kupffer cells to enable studies of immune- mediated toxicity of drug candidates (4); and the Brain-Chip incorporates microglia to enable studies of neuroinflammation – a process that is implicated in many neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease (5). Researchers at the Wyss Institute have also modeled the immune system by creating a Lymphoid Follicle-Chip (6), which they have used to recapitulate human immune function, and evaluate the efficacy of vaccines for flu and COVID-19.

How can researchers gain access to these new capabilities and use them in their own work?
 

First, researchers can work with our in-house service team of experts, who can design and execute a study to investigate the efficacy or toxicity of anti-inflammatory drug candidates for IBD. Second, they can bring Emulate Organ-on-Chip technology – which we call the Human Emulation System^® – into their own labs (7). We offer instrumentation to automate cell culture conditions, Bio-Kits that include the chips and primary human cells customers need to build the Colon Intestine- Chip, and robust protocols, training, and experimental support to help drive success. Whether the research is performed in our labs or in our customer’s labs, our hope is that these new capabilities can help researchers develop more effective therapeutics for IBD.