Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Extracellular Matrix for Repair of Gastrointestinal Mucosa

Keane, Timothy (2016) Extracellular Matrix for Repair of Gastrointestinal Mucosa. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Primary Text

Download (6MB)


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.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Keane, Timothykeanetim17@gmail.comTIK6
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBadylak, Stephen
Committee MemberBrown, Bryan Nbnb9@pitt.eduBNB9
Committee MemberStolz, Donna Bdstolz@pitt.eduDSTOLZ
Committee MemberHackam, David
Committee MemberWang, Yadongyaw20@pitt.eduYAW20
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


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item