Miguel Regueiro, MD, and Emina Huang, MD, on Identifying Targets for UC Therapies

In this video Dr Regueiro and Dr Huang, from the Cleveland Clinic, discuss the development of a novel disease model to identify targets for future ulcerative colitis therapeutic agents.

The objective of the study was to create an individualized model of ulcerative colitis using patient-derived tissues that incorporate both the epithelium (the surface cells) and the surrounding microenvironment. The researchers were able to demonstrate this for the first time.

The organoids resemble the parental tissues from which they came. The discovery that one of the inflammatory hormones of the immune system, CXCL8, was upregulated and could be diminished by a small molecule inhibitor demonstrated that the organoids created are dynamic and can respond to a drug. Therefore, these organoids may act as avatars for patients, permitting multiple therapeutic agents to be tested ex vivo.

Miguel Reguerio, MD, is chair of gastroenterology, hepatology, and nutrition and vice-chair for the Digestive Disease and Surgery Institute at Cleveland Clinic in Cleveland, Ohio. Emina Huang, MD, is a colorectal surgeon and researcher at Cleveland Clinic and its Lerner Research Institute. 

TRANSCRIPT

I'm Dr. Miguel Regueiro. I'm chair of gastroenterology, hepatology, and nutrition. I'm the vice-chair for Digestive Disease and Surgery Institute at Cleveland Clinic in Cleveland, Ohio.

This has been an exciting research. In a minute, you're going to hear from Dr. Huang about the technical aspects and the science, but the clinical applicability of precision medicine through her work for new treatment of ulcerative colitis is really exciting.

My name is Emina Huang, and I am a colorectal surgeon scientist here at the Cleveland Clinic. I'm here to report to you about a recent publication from the laboratory recently published in Nature Communications.

What spawned the work was an interest and understanding the relationships between epithelial cells and stroma in the development or pathogenesis of ulcerative colitis. The field has been limited by the capacity of having both epithelium on one hand and stroma or the surrounding neighborhood from the same patient, and understanding how these interact to cause the disease.

To date, most of the models that we've used are from people, and that's another great strength of our model, as we start with patients with the disease and have either been able to have the epithelial component or the stromal component.

We wanted a model that would have both components and be derived not from mice, but from patients, so that we could recapitulate the entire heterogeneity of the disease presentation. What we did was we borrowed from the Nobel Prize of work of Shinya Yamanaka. He won the Nobel Prize in 2012 and incidentally he started his career as a surgeon also, where he was able to reprogram adult somatic cells to pluripotency. In other words, he was able to create embryonic or fetal cells from adult cells by introducing 4 transcription factors known as Yamanaka factors.

We were able to prove that we were able to take adult somatic cells from either catalytic patients or normal colon and reprogram them to pluripotency. Then we borrowed technology from another one of our colleagues, who was able to drive directed differentiation to make gut.

The beauty of these pluripotent cells is they can make skin, they can conceivably make brain, they can make muscle, they can make gut. In our case, we push the differentiation to make gut, and indeed we were able to prove that in our model we were able to recapitulate colitic features from the fibroblasts that originated from patients with colitis, while from the patients that started with normal fibroblasts from the colon, we were able to recreate normal colon.

We tested these organoids that had both epithelium and the stroma. We tested them for what other molecular features they might have, and we were able to determine that they expressed a chemokine, or a hormone of the immune system called CXCL8.

We were able to then mitigate the colitic phenotype by using a chemical which antagonizes the CXCL8 receptor. We were able to mitigate the phenotypes of the catalytic or iPSC organoids, so that they looked more like normal colon organoids, both in the epithelium and the stroma. This, we feel, is a great discovery

The individual isolates retain their individual features, so that they look like their parents from which they came, and they have not only have stroma, what you might call fibroblasts, but we also have signatures that they might contain immune cells as well.

We feel this is a great advance in the field not only as a model, but because we have preserved the individual variation and how the disease presents itself. We think that this can be used as models for testing new therapeutics and for identifying new therapeutics targeting not only the epithelium, but the stroma.

Thanks for listening, and stay tuned for more from this model.