Fibrosis Directly Affects Disease Progression in IBD

Inflammatory bowel disease (IBD) is associated with deterioration of the gut epithelium, including loss of barrier function and alterations in various epithelial cell populations. At the same time, excessive deposition of extracellular matrix proteins such as collagen causes the basement membrane to stiffen.

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Massachusetts General Hospital researchers recently investigated how intestinal stiffening affects the growth and differentiation of intestinal stem cells (ISCs), which direct intestinal epithelium regeneration. Unexpectedly, they discovered intestinal stiffening and fibrosis are critical components of IBD pathogenesis—not negligible effects of inflammation as previously thought.

In Gastroenterology, Nima Saeidi, PhD, associate investigator in the Division of Gastrointestinal and Oncologic Surgery and associate professor of Surgery at Harvard Medical School, Shijie He, PhD, researcher in the Division and instructor in Medicine at Harvard Medical School, Peng Lei, PhD, research fellow in the Division, and colleagues explain how the findings could lead to new therapeutic strategies.

Methods

The researchers created a polyacrylamide–hydrogel matrix that recapitulated the anatomy of the gut epithelium: an open lumen with a layer of epithelial cells residing on the top surface of the basement membrane. This experimental setup allowed for the manipulation of tissue stiffness. ISCs and crypts were harvested from mouse small intestine and a long-term culture system was developed on top of the matrix.

As the organoids grew, the soft hydrogel surface buckled, forming a 2.5D curved surface that mimicked in vivo crypt morphology.

Results

Increasing matrix stiffness to the range observed in IBD patients:

• Substantially reduced leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5)+ ISCs, which activate the WNT signaling pathway, a family of proteins related to the development and renewal of small-intestinal epithelial tissue
• Allowed cells expressing the stem cell marker olfactomedin-4 (OLFM4) to replace LGR5+ ISCs, becoming dominant in the crypt region and extending into villus-like regions
• Promoted the differentiation of ISCs into goblet cells

All these changes were similarly observed in stiff colon samples from a mouse model of colitis and from IBD patients.

Other principal observations in the 2.5D organoids were:

• YAP, a critical regulator of cellular response to tissue stiffness, had divergent mechanistic roles in determining the ISC differentiation trajectory: cytoplasmic YAP expression induced by matrix stiffening drove the extension of OLFM4+ cells into villus-like regions, whereas nuclear YAP expression led to a loss of LGR5+ ISCs and increased differentiation toward goblet cells
• Matrix stiffening augmented ISC glucose demand and metabolism, and inhibiting glucose uptake on a stiff matrix led to a shift toward a soft matrix-like phenotype

Therapeutic Implications

These findings lead to two sets of conclusions. First, intestinal stiffening during IBD might influence the fate of ISCs via YAP-induced metabolic rewiring. Therefore, exploiting the metabolic vulnerability of the mechano-stimulated ISCs is potentially a novel strategy for treating IBD.

Second, OLFM4⁺ cells in the stiff colon may be capable of generating new crypts, which could be a pathogenic factor in colitis-associated colorectal adenocarcinoma. The signaling pathways involved in stiffening-induced OLFM4 extension might be clinical targets for that disease.

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