Mesenchymal stem cells or multipotent stromal cells (MSCs) are cells of mesodermal origin which are the presumptive progenitors of osteoblasts. First described in 1976 by Friedenstein, their role in tissue repair has been studied extensively. Recent evidence indicates Wnt signaling is important to this process in bone, and also implicates MSCs in development of osteolytic lesions in the B cell malignancy of multiple myeloma (MM). MM cells secrete the Wnt inhibitor Dkk1, which inhibits MSC osteogenic differentiation. The aim of these studies was to determine whether the effect of MM-derived Dkk1 promotes osteolytic lesions by inhibiting bone repair by MSCs. To this end, we explored the effect of Wnt in osteogenic cultures of MSCs, determined the effect of MM cells on MSC osteogenesis, and set up an animal model to test a potential treatment for MM which interrupts the effect of MM cells on bone repair. By developing a sensitive and high-throughput osteogenesis assay, we confirmed that Dkk1 inhibits MSC osteogenesis. Using the results from these studies, we developed a means to interrupt the synergy between MSCs and MM cells. Finally, we developed the first animal model for MM which recapitulates the bone effects using human MM cells in a rapid and predictable manner and showed that attenuation of the Dkk1 signal reduced the effect of MM cells on markers of bone resorption and repair. This work has furthered the understanding of the role of MSCs in bone repair, provides tools for examining the effect of compounds which affect bone repair, and demonstrates for the first time enhanced bone repair in vivo by promotion of Wnt signaling using a Dkk1 antagonist.
|Advisor:||Prockop, Darwin J.|
|Commitee:||Burow, Matthew, Flemington, Erik, Gregory, Carl A., Phinney, Don|
|School Location:||United States -- Louisiana|
|Source:||DAI-B 70/07, Dissertation Abstracts International|
|Subjects:||Molecular biology, Cellular biology|
|Keywords:||Animal model, Bone, Dkk1, Mesenchymal stem cells, Multiple myeloma, Stem cells, Wnt|
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