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Engineered Tracking and Delivery of Mesenchymal Stem Cells (MSCs)

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2013, Doctor of Philosophy, Case Western Reserve University, Biomedical Engineering.
Mesenchymal stem cells (MSCs) are tissue culture plastic adherent cells that are able to differentiate into multiple cell types, modulate the immune system, and aid in wound repair. These versatile cells are thus being investigated to treat a wide variety of different diseases such as graft vs. host disease, rheumatoid arthritis, myocardial infarction, and damaged cartilage. In addition, with genetic modification, MSCs can be used as drug delivery vehicles to treat cancer or as a cell replacement therapy to treat osteogenesis imperfecta. However, the delivery of MSCs to a target organ, and the delivery of stem cells in general, remains a major challenge. This thesis investigates the hypothesis that when MSCs are efficiently delivered into the circulation, they will home to sites of injury. First, MSCs were genetically modified by lentiviral transduction with a dual reporter gene vector containing monomeric red fluorescent protein and luciferase in order to track the cells in vivo in real time. It was found that polybrene, an additive commonly used during transduction, severely inhibited MSC proliferation. A new method was developed for efficient lentiviral transduction using protamine sulfate, and other techniques. MSC engraftment to sites of injury was investigated by delivering cells into mice irradiated on one leg, with the non-irradiated leg serving as an internal negative control. Delivery of the cells into the aortic arch resulted in initial cell distribution throughout the entire body and engraftment in only the irradiated leg as detected by bioluminescent imaging (BLI). The biolumescence increased over time, indicating that the engrafted MSCs proliferated in vivo. In contrast, cells delivered intravenously were trapped in the lungs with no engraftment. This homing is specific to MSCs, since it was not observed with kidney cells. Furthermore, aortic arch delivery was efficient, as engraftment was consistently observed with a dose of only 2.5 x 105 cells/mouse. Finally it was shown that MSCs are capable of being serially transplanted while maintaining their homing ability. Thus, this thesis demonstrates that MSCs can home and engraft at sites of injury from the circulation, that the homing is specific, and that the proper cell delivery method is critical for efficient cell engraftment. These results will aid in developing effective clinical MSC therapies.
Roger E. Marchant, PhD (Committee Chair)
Arnold I. Caplan, PhD (Advisor)
Horst von Recum, PhD (Committee Member)
James M. Anderson, MD, PhD (Committee Member)
Alison Hall, PhD (Committee Member)
281 p.

Recommended Citations

Citations

  • Lin, P. (2013). Engineered Tracking and Delivery of Mesenchymal Stem Cells (MSCs) [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1355278573

    APA Style (7th edition)

  • Lin, Paul. Engineered Tracking and Delivery of Mesenchymal Stem Cells (MSCs). 2013. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1355278573.

    MLA Style (8th edition)

  • Lin, Paul. "Engineered Tracking and Delivery of Mesenchymal Stem Cells (MSCs)." Doctoral dissertation, Case Western Reserve University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1355278573

    Chicago Manual of Style (17th edition)