New Model Aims to Study Intestinal Fibrosis in Crohn’s Disease

Intestinal fibrosis is a serious complication of Crohn’s disease (CD) without any approved therapies for prevention or treatment, outside of surgical intervention. A study at the annual Digestive Disease Week conference examined the feasibility of using induced pluripotent stem cell-derived human intestinal organoids from Crohn’s disease patients to model intestinal fibrosis.

In this exclusive MedPage Today video, lead author Christian Wong Valencia, PhD, a postdoctoral scientist at Cedars-Sinai Medical Center in Los Angeles, discusses the background and results of the study.

Following is a transcript of his remarks:

Our focus has been to develop a model of intestinal fibrosis using induced pluripotent stem cells [iPSCs]-derived human intestinal organoids that come from Crohn’s disease patients that have developed stricturing complications.

Our objective is to identify if there’s a transcriptomic gene signature that is characteristic from the patients that develop or will develop stricturing complications versus patients that did not develop stricturing complications. And what we have done is that we take their blood samples from patients with Crohn’s disease — a cohort with stricturing complications and a cohort without the complications, re-program them to become induced pluripotent stem cells and then direct them to become human intestinal organoids.

Now the neat thing from iPSC-derived organoids is that they develop mesenchymal cells, which is the cell type below intestinal epithelium, and the epithelium also from the intestinal lining. So what we can do then is separate them and generate mesenchymal-only cultures and epithelial-only cultures to evaluate their individual contribution to the fibrogenic phenotype. That’s how we have been working so far. And what we found is that each individual cell type has a different transcriptomic profile, and we have some hypothesis of how this is contributing to the development of fibrosis.

From the epithelial side, we found that once we induce fibrosis with specific cytokines, the response that the epithelial cells gives us is comparatively similar to what we will expect from the gene expression signature from strictured tissue from patients with Crohn’s disease. We have found that most of the genes that were identified in these intestinal epithelial organoids cluster or group into specific sets or signaling pathways that are associated with the communication and the amplification of the inflammatory and fibrogenic signal towards other cell types, such as the mesenchymal cells or the immune cells.

We believe that part of the role of intestinal epithelium is to communicate with and amplify the signal, recruit some cells from the mesenchymal and the immune compartment, and then continue with the development of the fibrogenic phenotype. Whereas for the mesenchymal component, we also detect several inflammatory and fibrogenic genes that have been clustered, we believe that this is what leads to the development of fibrosis in the patients with obstruction complications. And we are still working on outlining if there’s a specific subset of genes or a specific signaling pathway that is distinguishing the patients that will develop stricturing complications versus those which will not develop stricturing complications.

The clinical implications from this is that if then we can get a model of intestinal fibrosis directly from the patients, then maybe there is some predictive value that will allow us to anticipate which patient will develop strictures, which ones will not, and how we can better tailor their treatments so that we can prevent or halt the development of strictures and fibrosis as much as we can. Also, which medication we can give at which time point so that we can halt the development of resistance to these therapies.

Furthermore by outlining these gene signatures, what we can find is new potential drug targets that then we can develop compounds or develop treatments against it so that we can have more comprehensive therapy since there’s so far no way to treat fibrosis in the intestine. So if we find new pathways that are associated with the development of strictures and fibrosis, then we can find new candidate genes or new therapeutic candidate targets that then we can develop treatments against.