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Cardiogenic differentiation of induced pluripotent stem cells for regeneration of the ischemic heart

Buccini, Stephanie M.

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2013, PhD, University of Cincinnati, Medicine: Systems Biology and Physiology.
Ischemic heart disease is the number one cause of death worldwide. Excessive cardiomyocyte death occurs following myocardial infarction, thus triggering downstream signaling cascades that alter the physiological and morphological characteristics of the heart. Extensive fibrosis and dilation in the left ventricle significantly reduce cardiac function and ultimately lead to heart failure. Current therapies are only palliative and provide symptomatic relief; however, stem cell therapy holds the promise of replenishing damaged tissue with healthy, fully functional cardiomyocytes. Over the past decade, a variety of stem cells have been extensively studied for cardiac repair, including bone marrow stem cells, skeletal myoblasts, cardiac stem cells, as well as embryonic stem cells. Moreover, the Nobel Prize winning discovery that pluripotency can be induced in adult somatic cells lead to the rapid characterization and development of another stem cell source termed "induced pluripotent stem cells." The overall objective of this project was to reprogram bone marrow-derived mesenchymal stem cells (MSC) into induced pluripotent stem cells (iPSC) for utilization in generating an unlimited source of cardiovascular cells that could be used to treat ischemic heart disease. The central hypothesis was that induction of pluripotency in MSCs enhances angiomyogenic differentiation for effective regeneration and repair of the ischemic heart. This project was the first to establish that MSC-derived iPSCs (MiPS) effectively differentiate into beating cardiomyocytes that contribute to improved cardiac function and tissue regeneration in the infarcted heart. Moreover, our results show that MiPS significantly differ from embryonic stem cells in their transcriptional profiles, possibly due to maintenance of epigenetic memory in MiPS. Although both pluripotent stem cell types are morphologically similar and express a number of pluripotency-regulating factors, we have shown that MiPS differentially express a number of microRNAs which contributes to altered angiogenic potential of the cells. Finally, this study demonstrates that isolation of an Flk1+ cardiac progenitor population from MiPS reduces their risk of teratogenicity after transplantation and we develop an efficient method for angiomyogenic differentiation of Flk1 progenitors by treatment with vascular endothelial growth factor. In summary, this project has demonstrated that MSCs are an optimal cell source for deriving iPSC lines based on their pro-angiogenic and myogenic traits. Furthermore, this study assesses the safety of using MiPS cells for cardiac regeneration and demonstrates a safer approach to derive cardiac cells through MiPS-derived progenitors. Together, these studies validate the usefulness of deriving iPSCs from MSCs and provide a more detailed assessment of iPSCs and their cardiogenic differentiation properties as well as their ability to repair the ischemic heart.
John Lorenz, Ph.D. (Committee Chair)
Rafeeq Habeebahmed, Ph.D. (Committee Member)
Khawaja Haider, M.Pharm., Ph.D. (Committee Member)
Nelson Horseman, Ph.D. (Committee Member)
Walter Jones, Ph.D. (Committee Member)
Yana Zavros, Ph.D. (Committee Member)
179 p.

Recommended Citations

Citations

  • Buccini, S. M. (2013). Cardiogenic differentiation of induced pluripotent stem cells for regeneration of the ischemic heart [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1382373160

    APA Style (7th edition)

  • Buccini, Stephanie. Cardiogenic differentiation of induced pluripotent stem cells for regeneration of the ischemic heart. 2013. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1382373160.

    MLA Style (8th edition)

  • Buccini, Stephanie. "Cardiogenic differentiation of induced pluripotent stem cells for regeneration of the ischemic heart." Doctoral dissertation, University of Cincinnati, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1382373160

    Chicago Manual of Style (17th edition)