Keane, Timothy
(2016)
Extracellular Matrix for Repair of Gastrointestinal Mucosa.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Extracellular matrix (ECM) bioscaffolds have been shown to promote site-appropriate functional
tissue remodeling in multiple anatomic sites, including the gastrointestinal (GI) tract. Discovery
work over the past 2 decades has identified contributing mechanistic factors of ECM-induced
tissue remodeling to be the modulation of the innate immune response by the action of
embedded signaling molecules while naturally occurring cryptic peptide motifs released or
exposed during ECM degradation and remodeling simultaneously promote stem/progenitor cell
chemotaxis, proliferation, and differentiation. This immune stimulatory approach, paired with
rapid restoration of the GI mucosal tissue, represents a novel therapeutic strategy for treating
disease of the GI tract such as inflammatory bowel disease (IBD). The objective of the present
thesis was to determine the efficacy of ECM for the repair of GI mucosal tissue. First, ECM was
isolated from the proximal (esophagus) and distal (colon) of the GI tract to characterize spatial
differences in the biochemical and mechanical properties of GI ECM. Next, we measured the
effect of GI-ECM on epithelial cell remodeling and the inflammatory response. Finally, the
efficacy of ECM for treating colonic mucosal tissue was tested in a rat model of IBD. Results
show expected spatial changes in ECM along the GI tract with esophageal and colonic ECM
having unique properties. Exposure of intestinal epithelial cells to GI ECM in-vitro led to
enhanced epithelial cell remodeling and an increased barrier function. Macrophages exposed to
degradation products of GI-ECM in-vitro were shown to exhibit an immunoregulatory and antiinflammatory
phenotype. Finally, an enema hydrogel composed of GI ECM was shown
effectively treat a rodent model of IBD. We defined effective therapy according to two essential
physiologic processes that were positively directed by ECMH treatment. First, the colonic
epithelial barrier function, which protects the host from the relentless barrage of proinflammatory
luminal contents, was restored. Second, the pro-inflammatory state of tissue
macrophages, which propagate inflammation by releasing inflammatory cytokines, was
resolved. Together, this strategy represents a proactive therapeutic approach and is a distinct
departure from the immunosuppressive (defensive) and surgical (salvage) methods currently
used to treat IBD.
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Details
Item Type: |
University of Pittsburgh ETD
|
Status: |
Unpublished |
Creators/Authors: |
|
ETD Committee: |
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Date: |
16 September 2016 |
Date Type: |
Publication |
Defense Date: |
3 June 2016 |
Approval Date: |
16 September 2016 |
Submission Date: |
6 June 2016 |
Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
Number of Pages: |
266 |
Institution: |
University of Pittsburgh |
Schools and Programs: |
Swanson School of Engineering > Bioengineering |
Degree: |
PhD - Doctor of Philosophy |
Thesis Type: |
Doctoral Dissertation |
Refereed: |
Yes |
Uncontrolled Keywords: |
Extracellular matrix, inflammatory bowel disease, macrophage activation, barrier function |
Date Deposited: |
16 Sep 2017 05:00 |
Last Modified: |
16 Sep 2017 05:15 |
URI: |
http://d-scholarship.pitt.edu/id/eprint/28126 |
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