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The Role of CD44 Variant Isoforms in Gastric Regeneration and Disease

Bertaux-Skeirik, Nina

Abstract Details

2017, PhD, University of Cincinnati, Medicine: Systems Biology and Physiology.
Background: Chronic inflammation associated with persistent infection with Helicobacter pylori (H. pylori) is a major risk factor for the development of gastric ulcers and gastric cancer. Abnormal differentiation of the gastric mucosa is associated with cancer and may reflect a permanent alteration in the behavior of the stem cells, thus making the gastric stem cell a candidate H. pylori target. Furthermore, gastric cancer is the second leading cause of cancer-related deaths worldwide. Objective: To identify novel mechanisms in the development and maintenance of gastric diseases to potentially assess sensitivity to diverse therapeutics with a focus on patient response predictions. Major Findings: 1) CD44 plays a functional role in Helicobacter pylori-induced epithelial cell proliferation. CD44 has been shown to coordinate normal and metaplastic cell proliferation in the stomach, however the role of CD44 in H. pylori-induced proliferation is unclear. To assay changes in gastric epithelial cell proliferation in relation to the direct interaction with H. pylori, mouse and human-derived gastric organoid cultures were infected with the G27 H. pylori strain or a mutant G27 strain bearing cagA deletion (CagA::cat). Human organoids infected with H. pylori exhibited an induction in proliferation that was blocked with a peptide inhibitor specific to CD44. In a Mongolian gerbil model of H. pylori infection, animals treated with CD44 inhibitor Pep1 resulted in an inhibition of H. pylori-induced proliferation and atrophic gastritis. These data establish a functional role for CD44 in H. pylori-induced epithelial proliferation. 2) Patient-Derived In Vitro and In Vivo Organoid Models of Gastric Cancer. Among the populations of stem cells within the stomach that may be targeted during bacterial infection are cells expressing the cluster-of-differentiation (CD) CD44 cell surface receptor. Alternative mRNA splicing produces CD44 variant isoform 9 (CD44v9) that has been demonstrated to be a gastric cancer stem cell marker. H. pylori infection was associated with the robust emergence of CD44v9 in human stomach tissue. In normal gastric human organoids engineered to have a deletion of p53, CD44v9 expression was induced. Human-derived organoids derived from a patient with diffuse-type gastric cancer highly expressed CD44v9. CD44v9 marks a gastric stem-like cell population that emerges in response to H. pylori infection and is maintained within the tumor. These data demonstrate an in vivo and in vitro patient-derived organoid-based platform that may be used for personalized medicine. 3) CD44 variant isoform 9 emerges in response to injury and contributes to the regeneration of the gastric epithelium. CD44 variant isoforms (CD44v), emerges during regeneration of the gastric epithelium in response to injury. CD44v9 is expressed within Spasmolytic Polypeptide/TFF2-Expressing Metaplasia (SPEM) glands during gastric repair, but the function is unknown. Acetic acid injury was induced in CD44-deficient (CD44KO) and C57BL/6 (BL6) mice. Mouse-derived organoids expressing CD44v9 were transplanted at the ulcer site of CD44KO mice. Human-derived gastric organoids from elderly patients (>55 years) or young patients (14-20 years) were transplanted into NOD scid gamma (NSG) mice post-injury. Compared to BL6 mice that healed within 7 days post-injury, CD44KO mice exhibited loss of ulcer repair and gastric epithelial regeneration. Transplantation of CD44v9-expressing gastric organoids into the stomachs of CD44KO mice promoted ulcer repair. Compared to NSG mice exhibiting loss of CD44v9 expression and gastric repair in response to injury, transplantation of human-derived gastric organoids from young, but not aged stomachs promoted repair. These data indicate that CD44v9 marks a regenerative cell lineage during ulcer repair.
Yana Zavros, Ph.D. (Committee Chair)
Christian Hong, Ph.D. (Committee Member)
Nelson Horseman, Ph.D. (Committee Member)
Mario Medvedovic, Ph.D. (Committee Member)
Marshall Montrose, Ph.D. (Committee Member)
Jiang Wang, M.D. Ph.D. (Committee Member)
James Wells, Ph.D. (Committee Member)
180 p.

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Citations

  • Bertaux-Skeirik, N. (2017). The Role of CD44 Variant Isoforms in Gastric Regeneration and Disease [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504879114818203

    APA Style (7th edition)

  • Bertaux-Skeirik, Nina. The Role of CD44 Variant Isoforms in Gastric Regeneration and Disease. 2017. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504879114818203.

    MLA Style (8th edition)

  • Bertaux-Skeirik, Nina. "The Role of CD44 Variant Isoforms in Gastric Regeneration and Disease." Doctoral dissertation, University of Cincinnati, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504879114818203

    Chicago Manual of Style (17th edition)