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dc.contributor.authorHerberg, Samuel A.
dc.date.accessioned2014-05-15T19:19:32Z
dc.date.available2014-05-15T19:19:32Z
dc.date.issued2013-03en
dc.identifier.urihttp://hdl.handle.net/10675.2/317023
dc.description.abstractThe experiments performed for this dissertation tested the hypotheses that SDF-1β enhances osteogenic differentiation of BMSCs, promotes engraftment and bone formation following whole-body irradiation, and potentiates suboptimal BMP-2 osteoinduction in a model of acute bone injury. We used multipotent primary BMSCs from 18-month-old C57BL/6J mice, genetically modified to overexpress SDF-1β, to ask whether SDF-1β played a role in cell survival and osteogenic differentiation of BMSCs in vitro. Our studies revealed that SDF-1β protected BMSCs from oxidative stress through increasing autophagy and decreasing apoptosis, independent from potential effects on cell proliferation. In support of the hypothesis we also found that SDF-1β enhanced calcium mineral deposition (independent of BMP-2 co-stimulation), upregulated key osteogenic markers, and increased phosphorylation of intracellular Erk1/2 and Smad1/5/8, thereby potentiating BMP-2 signal transduction during osteogenic differentiation, which was attenuated by blocking CXCR4 signaling. We next inquired whether SDF-1β promotes BMSC engraftment and new bone formation. Using direct tibial transplantation in irradiation-preconditioned animals, we found that SDF-1β enhanced new trabecular bone formation upon local BMSC transplantation. The data furthermore suggested that the differential proteolytic clearance of SDF-1 splice variants in the systemic and local environment following myeloablative injury may be an important determinant in the success of stem cell therapy protocols. The suggestion that SDF-1β could regulate BMP-2 osteoinduction through regulating CXCR4 signaling was compelling because several studies have reported a comparable effect using SDF-1α. We examined the direct contribution of SDF-1β to BMP-2 osteoinduction in a critical-size calvaria osteotomy model and found a dose-dependent ability of SDF-1β to potentiate suboptimal BMP-2-induced bone formation to levels comparable to those obtained with the 10-fold higher optimal/benchmark BMP-2 dose, which was blunted by perturbing CXCR4 signaling. These in vitro and in vivo findings expand our understanding of BMP-2 osteoinduction and implicate osteogenesis-enhancing properties of SDF-1β pointing towards its translational potential for cell therapy and regenerative medicine applications. It appears feasible for SDF-1β to improve bone regeneration in a variety of orthopaedic situations and ultimately reduce the burden of musculoskeletal injuries.
dc.relation.urlhttp://search.proquest.com/docview/1370320976?accountid=12365en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.en
dc.subjectStromal Cell-deriveden
dc.subjectBone Marrowen
dc.subjectOsteogenicen
dc.subjectDepartment of Cellular Biology and Anatomyen
dc.titleThe Role of Stromal Cell-Derived Factor-1Β in Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stem/Stromal Cells and Bone Formationen
dc.typeDissertationen
dc.contributor.departmentDepartment of Cellular Biology and Anatomyen
dc.description.advisorHill, William D.en
dc.description.degreeDoctor of Philosophy (Ph.D.)en
dc.description.committeeErgul, Adviye; Schoenlein, Patricia V.; Bollag, Wendy B.; Shi, Xingming; Hamrick, Mark W.en


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