Engineering Mesenchymal Stem Cell Based Gene Delivery Systems
IBB Breakfast Club Seminar 2010-2011 Series Kickoff - Michelle Dawson, PhD - Assistant Professor, School of Chemical & Biomolecular Engineering
"Engineering Mesenchymal Stem Cell Based Gene Delivery Systems"
Mesenchymal stem cells (MSCs) are bone marrow-derived adult stem cells that are involved in wound healing and tissue regeneration. MSCs are good candidates for the development of cell-based therapeutics. They can be easily harvested from bone marrow, expanded in the lab, genetically manipulated, and differentiated into different types of tissues. However, ex vivo expansion of MSCs alters their morphology limiting their mobility after reinfusion. In vivo, the recruitment of MSCs to diseased or tumor tissues is mediated by pro-angiogenic proteins that are released by tumors or wound tissues and circulate in the blood. Previous studies have demonstrated that MSC treatment with pro-angiogenic proteins results in increased in vitro cell migration. However, little is known about the effects of these proteins on the mechanical properties of MSCs. We hypothesized that pro-angiogenic proteins, secreted by tumor or wound tissues, stimulate MSCs, inducing their migration, through rapid modification in cytoskeletal rigidity. The mechanical response of a cell to chemical or physical stimuli is regulated by the cytoskeleton, a dynamic network of protein filaments extending throughout the cytoplasm. The cytoskeletal filaments are linked to adhesion molecules in the extracellular environment by focal adhesion complexes. The organization of cytoskeletal filaments and focal adhesion complexes changes rapidly during cell migration. Using quantitative real-time microscopy techniques, including particle tracking microrheology and time-lapsed fluorescent microscopy, we monitored the effects of tumor-secreted soluble factors on intracellular rheology, cytoskeletal organization (including cytoskeletal filaments and focal adhesion proteins), and interaction with cell adhesion molecules. Together these techniques will be used to identify the mechanical and adhesive properties of migratory MSCs. Optimized MSCs, found to possess the mechanical properties associated with increased migration, will be tested in vivo for accumulation in tumors and then engineered to produce therapeutic proteins that will be used to treat cancer in mice.
Coffee and continental breakfast will be served.