Date of Award
2014
Embargo Period
8-1-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Microbiology and Immunology
College
College of Graduate Studies
First Advisor
James S. Norris
Second Advisor
Zihai Li
Third Advisor
Kelley Argraves
Fourth Advisor
Amanda C. Larue
Fifth Advisor
Christina Voelkel-Johnson
Abstract
Mesenchymal stromal cells (MSCs) are a multipotent cell population acquired most prominently from bone marrow with the capacity to differentiate into osteoblasts, chondrocytes, adipocytes, cardiomyoctes, fibroblasts and other cell types. The immunoprivileged nature of these cells combined with their ability to home to sites of injury enhances therapeutic interest in this stem cell population. Phase I‐III clinical trials are being conducted evaluating the therapeutic potential of MSCs in graft vs. host disease, following acute myocardial infarction, multiple sclerosis, and bone and cartilage diseases. Sphingosine 1‐phosphate (S1P) is a biologically active sphingolipid impacting proliferation, apoptosis, inflammation, and angiogenesis. Interactions with 5 G‐protein coupled S1P receptors (S1PR1‐5) mediate in part these functions. Whereas S1PR1‐R3 are ubiquitously expressed, S1PR4 and S1PR5 have more limited expression. This project seeks to assess the role of the S1PRs in the maintenance of a multipotent MSC population and the impact of modulation of S1PR2 on the progression of prostate cancer. Inhibition of S1PR2 results in increased MSC clonogenicity, migration, and proliferation. The increased Erk phosphorylation observed with S1PR2 inhibition is required for these increases in migration and proliferation. Furthermore, decreased S1PR2 expression decreases the differentiation of MSCs into adipocytes and mature osteoblasts that may be the result of increased expression of MSC pluripotency factors including Nanog, Sox9, and Oct4. Inhibition of S1PR1 and S1PR3 in contrast does not impact MSC migration or Erk activation although increased proliferation is observed. In the study, we describe the essential role of S1PR2 in MSC differentiation pathways through modification of pluripotency factors. We propose a MAPK dependent mechanism through S1PR2 inhibition that promotes equally pluripotent MSC proliferation in a way that can be exploited for better ex vivo MSC expansion in autologous MSC transplant. When MSCs are co-cultured with murine prostate cancer cells, an increased stem cell population is observed with greater proliferation of cancer cells following inhibition of S1PR2. We therefore proposed that S1PR2 in MSCs within the tumor microenvironment enhances the metastatic potential of tumors.
Recommended Citation
Marrison, Sarah Tucker, "Sphingosine 1-phosphate Receptor Signaling in Mesenchymal Stromal Cells" (2014). MUSC Theses and Dissertations. 508.
https://medica-musc.researchcommons.org/theses/508
Rights
All rights reserved. Copyright is held by the author.
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