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Researchers Develop New Model to Test Mechanisms of Penetrating Fibrosis

Dr. Stappenbeck’s team has found interconnectivity between inflammatory fibroblasts and the molecular features of penetrating fibrosis in Crohn’s disease.

08/17/2021



Researchers led by Thaddeus Stappenbeck, MD, PhD, chair of the Department of Inflammation & Immunity, have developed a new preclinical model with features of mesenteric fibrosis that are similar to what is found in Crohn’s disease patients (CD). Using clinical data coupled with the new model may help researchers identify new therapeutic targets to prevent or treat fibrosis in CD. 

According to the study published in Gut, researchers investigated the molecular features of penetrating fibrosis, which is one of the severe complications of CD. This form of fibrosis occurs primarily outside of the intestine (in the mesentery), although it’s been shown to be interconnected to the fibrosis in all layers of the intestine.

In these areas, there is an expanded population of cells called fibroblasts. Prior studies conducted by other research groups have identified unique inflammatory features of fibroblasts that are suspected drivers of CD development and progression. Using data from these studies, the Stappenbeck team investigated the signature of these intestinal fibroblasts and other elements in penetrating fibrosis.

“We started the project using clinical samples to characterize the histological and molecular signatures of fibrosis in Crohn’s disease patients,” said Dr. Stappenbeck.  “We were particularly interested in studying tissues not accessible by endoscopic biopsies, including the mucosa through the muscle wall and into the surrounding fat.”

Fibrosis signature in CD can predict response to traditional therapy

The researchers studied samples of healthy and damaged intestinal tissues from patients with CD, comparing fibrotic mesenteric fat with areas of unaffected mesenteric fat for each patient. They identified a set of transcripts (byproducts of DNA transcription) that defined penetrating fibrosis, which were commonly found in patients with severe disease.

With a better understanding of the clinical and molecular features of mesenteric fibrosis in CD patients, the researchers developed a mouse model that accurately mirrors features of penetrating fibrosis that occurs in CD. The team’s new model offers an opportunity for researches to evaluate genetic and pharmacologic approaches to treat intestinal fibrosis.  

They then developed a molecular signature of penetrating fibrosis based on both human and preclinical data. The common signature was useful as a tool that could predict responsiveness to certain therapeutics like anti-TNF biologics, drugs used to treat inflammatory diseases such as rheumatoid arthritis and Crohn’s disease.

Developing new therapeutics

“Moving forward, we hope that other teams will be able to use our model to test both mechanisms of penetrating fibrosis through genetic modifications or potential therapeutics that can either prevent fibrosis or alter its formation or course,” said Dr. Stappenbeck. 

The study was a close collaboration between Dr. Stappenbeck and researchers from Washington University School of Medicine in St. Louis, including co-authors Ta-Chiang Liu, MD, PhD; Yongjian Liu, PhD; Charles Whitehurst, PhD; Frank Li, PhD; and Shanshan Xiong, MD, a gastroenterologist-in-training who developed the concept for the experimental mouse model. The study was also conducted in partnership with Boerhinger-Ingelheim.




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