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dc.contributor.authorBogers, Sophie Helenen_US
dc.date.accessioned2018-01-12T07:00:20Z
dc.date.available2018-01-12T07:00:20Z
dc.date.issued2017-04-19en_US
dc.identifier.othervt_gsexam:10695en_US
dc.identifier.urihttp://hdl.handle.net/10919/81746
dc.description.abstractOsteoarthritis (OA) is a degenerative disease of diarthrodial joints causing pain and loss of joint function. Etiology is heterogeneous, but commonly involves inflammation arising from impairment of normal tissue homeostasis and/or function. A cycle of low-grade inflammation and global tissue degradation causes alteration of tissue morphology and function via primary mechanisms or inability to withstand physiological forces. Current therapies variably ameliorate symptoms but do not modify progression. Mesenchymal stem cells (MSCs) have multi-modal properties but are ineffective in ameliorating equine OA. However, anti-inflammatory activities of bone marrow derived MSCs (BMSCs) are enhanced by three-dimensional spheroid culture so equine BMSC (eBMSC) spheroids could inhibit intra-articular inflammation. The overarching hypothesis is that eBMSCs can be enhanced to produce an allogeneic eBMSC therapy that inhibits intra-articular inflammation. In vitro experiments compared differences in anti-inflammatory phenotype between spheroid and traditionally cultured monolayer eBMSCs, the viability and health of eBMSC spheroids administered through needles, and the effects of allogeneic donor on the anti-inflammatory potential of eBMSC spheroids. A model of equine LPS induced synovitis was used to investigate anti-inflammatory efficacy of spheroid eBMSCs compared to placebo or monolayer eBMSCs in vivo. eBMSCs aggregate into spheroids that have stable stem cell marker expression with increased secretion and gene expression of IL-6 and PGE2, and gene expression of SDF-1 and TSG-6. IFN𝛾 and TNFα were not produced by eBMSC spheroids and IL-10 production varied between individuals. Spheroids maintain higher viability and lower senescence than monolayer eBMSCs after injection through a needle and form in high-throughput culture without detrimental effects on expression of TSG-6, IL-6 and PGE synthases that denote an anti-inflammatory phenotype. Additionally, there is significant variation in this phenotype depending on the eBMSC donor. eBMSC spheroids reduced total nucleated cell counts and objective lameness measurements at peak levels of intra-articular inflammation compared to monolayer cultured eBMSCs in vivo. In summary, spheroids increase anti-inflammatory potential of eBMSCs and are practical for clinical use. Increased anti-inflammatory efficacy was demonstrated in a model of in vivo inflammation. This dissertation provides an understanding of the anti-inflammatory activities of eBMSC spheroids that can be used to develop an OA therapy.en_US
dc.format.mediumETDen_US
dc.publisherVirginia Techen_US
dc.rightsThis item is protected by copyright and/or related rights. Some uses of this item may be deemed fair and permitted by law even without permission from the rights holder(s), or the rights holder(s) may have licensed the work for use under certain conditions. For other uses you need to obtain permission from the rights holder(s).en_US
dc.subjectOsteoarthritisen_US
dc.subjectsynovitisen_US
dc.subjectmesenchymal stem cellsen_US
dc.subjectbiologic therapiesen_US
dc.subjectregenerative medicineen_US
dc.titleTurning Round: Optimizing the Anti-Inflammatory Properties of Equine Bone Marrow Derived Mesenchymal Stem Cells for Osteoarthritis Through Three-Dimensional Cultureen_US
dc.typeDissertationen_US
dc.contributor.departmentVeterinary Medicineen_US
dc.description.degreePh. D.en_US
thesis.degree.namePh. D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen_US
thesis.degree.disciplineBiomedical and Veterinary Sciencesen_US
dc.contributor.committeechairBarrett, Jennifer G.en_US
dc.contributor.committeememberFurr, Martin O.en_US
dc.contributor.committeememberEyestone, Willard H.en_US
dc.contributor.committeememberWhite, Nathaniel A.en_US
dc.contributor.committeememberByron, Christopher R.en_US


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