Intestinal Fibrosis Role in Inflammatory Bowel Disease Discovered

Intestinal fibrosis and stiffening are critical components of inflammatory bowel disease (IBD) pathogenesis, says study.

In inflammatory bowel disease (IBD), intestinal fibrosis was found to have a effect on disease progression, says study. Intestinal fibrosis is a common feature of inflammatory bowel disease (IBD) and the primary cause of end-stage organ failure.

The investigation was spearheaded by Nima Saeidi, PhD, Associate Professor of Surgery at the Massachusetts General Hospital (MGH) and Harvard Medical School, along with co-first authors, Shijie He, PhD, and Peng Lei, PhD.

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Increased expression of stem cell marker OLFM4 may have implications for the development of colitis-associated colorectal cancer.

The critical question posed by the investigators was how tissue stiffening influences the growth and differentiation of intestinal stem cells, which fuel the regeneration of intestinal epithelium?

This was addressed by developing a new in vitro platform, which allowed intestinal organoids to be cultured on an open lumen, planar system that could be manipulated experimentally.

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The platform permitted the use of soft yet “tunable” substrates with biophysical properties mimicking native tissue, facilitating the long-term growth and differentiation of intestinal stem cells, similar to native epithelium.

Saiedi and colleagues discovered that upon elevating substrate stiffness to a similar range observed in IBD patients, both the number and capacity of stem cells to maintain homeostasis and cellular composition of the epithelium were potently reduced.

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Concomitantly, the stem cells preferentially differentiated into goblet cells, leading to epithelial deterioration. Similar phenotypes were also noted in mouse models of IBD as well as in samples from human patients.

The investigators concluded that interfering with the molecular machinery involved in the cellular sensing of stiffness conferred protection against the detrimental effects of fibrosis and stiffening.

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The scientists also observed that despite the significant reduction in a specific population of stem cells, stiffening led to the expansion of another stem cell marker (OLFM4) outside the stem cell zone.

Source-Eurekalert