Role of High MUC2 Production in Colonic Goblet Cell Apoptosis and Wound Healing

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atmire.migration.oldid5901
dc.contributor.advisorChadee, Kris
dc.contributor.authorTawiah, Adelaide Ama
dc.contributor.committeememberMcCafferty, Donna-Marie
dc.contributor.committeememberDeVinney, Rebekah
dc.date.accessioned2017-08-29T17:30:19Z
dc.date.available2017-08-29T17:30:19Z
dc.date.issued2017
dc.date.submitted2017en
dc.description.abstractMUC2 mucin is produced by goblet cells, which forms the protective mucus blanket overlying the intestinal epithelium as the first line of innate host defense. MUC2 forms a physical barrier between the luminal contents and epithelium as a protective shield. Under normal physiological conditions, goblet cells produce MUC2 continuously to replenish the mucus blanket and maintain epithelial barrier function. However, in inflammatory bowel disease (IBD) and infectious colitis, MUC2 mucin is hyper secreted that leads to a phenomenon commonly referred to as ‘goblet cell depletion’ and eventual injury to the epithelium. It remains unclear however, how MUC2 production affects this phenomenon and whether goblet cells undergo increased endoplasmic reticulum (ER) stress and apoptosis in response to high MUC2 biosynthesis and secretion, which could explain how ‘goblet cell depletion’ occurs. In this study, I investigated the role of high MUC2 mucin production in goblet cell-induced ER stress, susceptibility to apoptosis and restitution following injury. Two cells lines were used; a high and low MUC2-producing human goblet cell-like cell lines designated HT29-H and HT29-L, respectively. Goblet cell ER stress and apoptosis were also quantified during early onset of DSS-induced colitis in C57BL/6 and Math1M1GFP mice. Compared to HT29-L, HT29-H cells showed significant increase in ER stress and apoptosis in response to ER stressors and apoptosis-inducing agents. Increased ER stress and apoptosis were dependent on reactive oxygen species (ROS) as inhibition of ROS significantly alleviated basal and tunicamycin- and thapsigargin-induced ER stress and rescued cells from apoptosis. DSS-induced colitis caused early hyper secretion of mucus and severe ER stress and apoptosis of goblet cells at the early onset of colitis. Increased MUC2 production in HT29-H cells inhibited production of growth factors and enzymes (FGF1, FGF2, VEGF-C, MMP-1) and intracellular signalling pathways (MMP-1, MAPK/ERK) critical for wound repair. As a result, HT29-H cells migrated significantly slower than HT29-L cells in epithelial restitution. This study have unravelled that high MUC2 biosynthesis during intestinal inflammatory diseases increases goblet cell susceptibility to ER stress and apoptosis, leading to goblet cell depletion, mucus barrier dysfunction and impaired goblet cell restitution and mucosal repair.en_US
dc.identifier.citationTawiah, A. A. (2017). Role of High MUC2 Production in Colonic Goblet Cell Apoptosis and Wound Healing (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/27679en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/27679
dc.identifier.urihttp://hdl.handle.net/11023/4038
dc.language.isoeng
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectImmunology
dc.subject.otherMUC2
dc.subject.othergoblet cells
dc.subject.otherApoptosis
dc.subject.otherER stress
dc.subject.otherwound healing
dc.titleRole of High MUC2 Production in Colonic Goblet Cell Apoptosis and Wound Healing
dc.typedoctoral thesis
thesis.degree.disciplineMicrobiology & Infectious Diseases
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
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