Human mesenchymal stem cells are a class of adult multipotent cells that are of interest to researchers for their clinical potential. While this cell type has been intensely investigated, there is still a significant amount to be learned about how these cells function. The presented studies utilized small molecular compounds to investigate the abilities of hMSCs. Project one investigated the roles matrix metalloproteinases (MMPs) play in adipogenic differentiation of hMSCs. MMPs are a family of metzincin proteinases that cleave the extracellular matrix (ECM), an activity that is critical to the differentiation process. These studies utilized the novel YHJ series of mercaptosulfonamide-based MMP inhibitors, which display high selectivity and potency for intermediate and deep pocket MMPs. Differentiation assays, kinetic assays, and qPCR were employed to characterize these inhibitors and determine their affect upon adipogenesis. Even though the YHJ MMPIs are not as stable as the hydroxamate-based MMPI GM6001, they produced comparable effects. Reduction in Lipid accumulation was also comparable to inhibition of peroxisome-proliferator activated receptor gamma (PPARĪ³) with the antagonist T0070907. Moreover, MMP inhibition was able to suppress lipid accumulation in cells co-treated with Troglitazone, a potent agonist of PPARĪ³. This is important as MMP inhibition is a potential avenue for obesity treatment research. Finally, the selectivity provided by the YHJ MMPIs allowed for the identification of MMP-3 (stromelysin-1) as a possible regulator of adipogenesis. Project two investigated hMSC resistance to the apoptotic effects of chemotherapeutic drugs. This has been of major interest, as hMSCs can confer resistance to tumor microenvironments. However, the effects of internalized chemotherapeutics upon hMSCs remain largely unexplored. Cellular viability and proliferation assays, combined with different biochemical approaches, were used to investigate the effects of Paclitaxel exposure upon hMSCs. The results indicate that hMSCs are highly resistant to the cytotoxic effects of Paclitaxel treatment, even though there was no detectable expression of the efflux pump P-glycoprotein, the usual means by which a cell resists Paclitaxel treatment. Moreover, Paclitaxel treatment induces hMSCs to adopt a non-proliferative fibroblastic state, as evidenced by changes to morphology, cellular markers, and a reduction in differentiation potential that is not directly coupled to the cytoskeletal effects of Paclitaxel. Taken together, these results show that Paclitaxel treatment does not induce apoptosis in hMSCs, but does induce quiescence and phenotypic changes. / A Dissertation submitted to the Institute of Molecular Biophysics in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Summer Semester 2015. / June 29, 2015. / Adipogenesis, Drug Resistance, Matrix Metalloproteinases, Mesenchymal Stem Cells, MMP Inhibitors, Paclitaxel / Includes bibliographical references. / Qing-Xiang Sang, Professor Directing Dissertation; Gregory Dudley, University Representative; Michael Roper, Committee Member; Timothy M. Logan, Committee Member; Yan Li, Committee Member.
| Identifer | oai:union.ndltd.org:fsu.edu/oai:fsu.digital.flvc.org:fsu_273630 |
| Contributors | Bosco, Dale Braxton (authoraut), Sang, Qing-Xiang Amy (professor directing dissertation), Dudley, Gregory B. (university representative), Roper, Michael Gabriel (committee member), Logan, Timothy M., 1961- (committee member), Li, Yan (committee member), Florida State University (degree granting institution), College of Arts and Sciences (degree granting college), Program in Molecular Biophysics (degree granting department) |
| Publisher | Florida State University, Florida State University |
| Source Sets | Florida State University |
| Language | English, English |
| Detected Language | English |
| Type | Text, text |
| Format | 1 online resource (153 pages), computer, application/pdf |
| Rights | This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). The copyright in theses and dissertations completed at Florida State University is held by the students who author them. |
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