You could be reading the full-text of this article now if you...

If you have access to this article through your institution,
you can view this article in

Matrix Stiffness Corresponding to Strictured Bowel Induces a Fibrogenic Response in Human Colonic Fibroblasts

Johnson, Laura A. BS*; Rodansky, Eva S. MS*; Sauder, Kay L. BS*; Horowitz, Jeffrey C. MD; Mih, Justin D. PhD; Tschumperlin, Daniel J. PhD; Higgins, Peter D. MSc, MD, PhD*

Inflammatory Bowel Diseases:
doi: 10.1097/MIB.0b013e3182813297
Original Basic Science Articles
Abstract

Background: Crohn's disease is characterized by repeated cycles of inflammation and mucosal healing which ultimately progress to intestinal fibrosis. This inexorable progression toward fibrosis suggests that fibrosis becomes inflammation-independent and auto-propagative. We hypothesized that matrix stiffness regulates this auto-propagation of intestinal fibrosis.

Methods: The stiffness of fresh ex vivo samples from normal human small intestine, Crohn's disease strictures, and the unaffected margin were measured with a microelastometer. Normal human colonic fibroblasts were cultured on physiologically normal or pathologically stiff matrices corresponding to the physiological stiffness of normal or fibrotic bowel. Cellular response was assayed for changes in cell morphology, α-smooth muscle actin staining, and gene expression.

Results: Microelastometer measurements revealed a significant increase in colonic tissue stiffness between normal human colon and Crohn’s strictures and between the stricture and adjacent tissue margin. In Ccd-18co cells grown on stiff matrices corresponding to Crohn’s strictures, cellular proliferation increased. Pathologic stiffness induced a marked change in cell morphology and increased α-smooth muscle actin protein expression. Growth on a stiff matrix induced fibrogenic gene expression, decreased matrix metalloproteinase, and proinflammatory gene expression and was associated with nuclear localization of the transcriptional cofactor MRTF-A.

Conclusions: Matrix stiffness, representative of the pathologic stiffness of Crohn’s strictures, activates human colonic fibroblasts to a fibrogenic phenotype. Matrix stiffness affects multiple pathways, suggesting that the mechanical properties of the cellular environment are critical to fibroblast function and may contribute to auto-propagation of intestinal fibrosis in the absence of inflammation, thereby contributing to the intractable intestinal fibrosis characteristic of Crohn’s disease.

In Brief

Article first published online 14 March 2013

Author Information

*Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan;

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; and

Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts.

Reprints: Peter D. Higgins, MSc, MD, PhD, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Medical Center Medical Science Research Building 1, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5682 (e-mail: phiggins@med.umich.edu).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ibdjournal.org).

Supported by a NIH K08DK080172-01 award to P. D. Higgins and a NIH R01HL105489 award to J. C. Horowitz.

The authors have no conflicts of interest to disclose.

Received August 06, 2012

Accepted September 06, 2012

© Crohn's & Colitis Foundation of America, Inc.

You currently do not have access to this article.

You may need to:

Note: If your society membership provides for full-access to this article, you may need to login on your society’s web site first.