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Title

Mechanisms for Colonic Mucosal Wound Repair

Date of Award

Spring 5-15-2015

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

The studies outlined in this thesis provide several new insights into mesenchymal and epithelial pathways necessary for colonic mucosal repair. We found that maximal expression of Ptgs2 in mesenchymal stromal cells was required for epithelial restitution and smooth muscle survival after colonic biopsy injury. We screened and identified Igf2bp1 as a novel Ptgs2 mRNA-binding protein required for maximal Ptgs2 expression. We next determined that the prostaglandin PGI2 was necessary to prevent smooth muscle necrosis. PGI2 functioned in our model by stimulating angiogenesis and preventing wound bed hypoxia. To rescue the angiogenesis and muscle loss defects in PGI2 receptor-deficient mice, we systemically and locally injected colonic mesenchymal stem cells. In contrast with systemically-injected cells, locally-injected MSCs migrated to wounds and stimulated repair. We next screened wound-associated epithelial cells and identified mesothelin as an epithelial gene expressed only after biopsy injury. We found that mesothelin was required for granulation tissue formation after colonic biopsy injury and was required for maximal polyp growth in APCMin/+ mice. Overall, this work describes mesenchymal- and epithelial-derived factors that are important for wound repair after colonic mucosal injury. Understanding the complex interactions for colonic wound repair will lead to better treatments for intestinal diseases such as inflammatory bowel disease.

Language

English (en)

Chair and Committee

Thaddeus S Stappenbeck

Committee Members

Gaya Amarasinghe, Robert Schreiber, William Stenson, Emil Unanue, Wayne Yokoyama

Comments

Permanent URL: https://doi.org/10.7936/K7S75DGX

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