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dc.contributor.authorCotter, Maura L.
dc.date.accessioned2012-08-27T20:39:09Z
dc.date.available2015-04-10T10:00:13Z
dc.date.issued2012-08-27
dc.date.submittedJuly 2012
dc.identifier.urihttp://hdl.handle.net/1928/20974
dc.description.abstractThe spatial organization and dynamics of proteins and lipids within the cell membrane is important for the regulation of cell signaling, adhesion, and cell communication. Within the bone marrow niche, communication between hematopoietic stem/progenitor cells (HSPCs) and niche cells is essential for regulating their proliferation, differentiation, and survival. Our previous work has ascertained that HSPCs utilize a polarized domain on the plasma membrane that serves as the contact site with osteoblasts, which are important members of the bone marrow niche. Using human primary CD34+ stem/progenitor cells and the progenitor-like KG1a cell line, we found this domain to be enriched in the specific tetraspanin proteins, CD63, CD81, and CD82. Tetraspanins are multi-spanning membrane proteins that act as scaffolds for the organization of membrane domains important for regulating adhesion and signaling. CD82 is of particular interest, as it is highly expressed on HSPCs and downregulated during HSPC differentiation. Our characterization of CD82 function using CD82-blocking antibodies revealed a significant decrease in adhesion of HSPCs to niche cells as well as in the in vivo homing and engraftment capabilities of these cells. To determine the molecular mechanisms of CD82’s role in adhesion, we have generated CD82 overexpression and knockdown cell lines using the KG1a background. Our data indicate that the level of CD82 expression positively correlates with the extent of adhesion to fibronectin and osteoblasts but has no effect on binding to collagen I or laminin. The increase in adhesion we observed with CD82 overexpression was inhibited by the VLA-4-specific peptide, LDV, indicating a potential role for the VLA-4 (α4β1) integrin. Investigations into potential CD82-mediated mechanisms of VLA-4 regulation have revealed that CD82 regulates both the expression and avidity of VLA-4 but does not regulate its affinity. Taken together, the VLA-4 expression and avidity changes could account for the observed adhesion changes with differing CD82 expression levels. Finally, assessment of CD82 palmitoylation using KG1a CD82 palmitoylation mutant cells revealed that palmitoylation may be required for the CD82-induced changes in adhesion.en_US
dc.language.isoen_USen_US
dc.subjectHematopoietic Stem Cellen_US
dc.subjectBone Marrowen_US
dc.subjectNicheen_US
dc.subjectOsteoblasten_US
dc.subjectFibronectinen_US
dc.subjectAdhesionen_US
dc.subjectIntegrinen_US
dc.subjectα4β1en_US
dc.subjectVLA-4en_US
dc.subjectTetraspaninen_US
dc.subjectCD82en_US
dc.subject.lcshCellular signal transduction.
dc.subject.lcshCell membranes.
dc.subject.lcshHematopoietic stem cells.
dc.subject.lcshOsteoblasts.
dc.subject.lcshCell adhesion.
dc.subject.lcshIntegrins.
dc.subject.lcshFibronectins.
dc.titleCD82 Regulation of Hematopoietic Stem/Progenitor Cell - Niche Adhesionen_US
dc.typeThesisen_US
dc.description.degreeBiomedical Sciencesen_US
dc.description.levelMastersen_US
dc.description.departmentUniversity of New Mexico. Biomedical Sciences Graduate Programen_US
dc.description.advisorGillette, Jennifer
dc.description.committee-memberBuranda, Tione
dc.description.committee-memberCannon, Judy
dc.description.committee-memberHartley, Rebecca
emb.embargo.terms2014-08-31


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