Cell-based therapies for ischemic cardiomyopathy : investigations of intramyocardial retention and safety of high dose intracoronary delivery of c-kit positive cardiac progenitor cells, and therapeutic utility of a novel population of cardiac mesenchymal stem cells expressing stage-specific embryonic antigen-3 (SSEA-3).
Date on Master's Thesis/Doctoral Dissertation
Physiology and Biophysics
Physiology and Biophysics, PhD
Committee Co-Chair (if applicable)
stem cell; cardiac repair; cardiomyopathy
Over the last decade attempts at reducing morbidity and mortality of patients with chronic heart failure have been made via the development and implementation of novel cell based therapies. Substantial advances in cell based therapies with indications of efficacy have been shown along with a robust safety profile. Despite these advances, there is a substantial unmet need for novel therapies, specifically addressing repair and regeneration of the damaged or lost myocardium and its vasculature. Accordingly, cardiac cell-based therapies have gained attention. Various cell-types have been utilized, including bone marrow-derived mononuclear cells, bone marrow-derived mesenchymal stem cells, mobilized CD34+ cells, and more recently, cardiosphere-derived cells and cardiac-derived c-kit positive progenitor cells. Early studies have suggested a potential of cell-based therapies to reduce cardiac scar size and to improve cardiac function in patients with ischemic cardiomyopathy. However, variability of results has been observed necessitating improvement of current methodologies related to optimizing the cell type(s), infusion techniques, timing, dosage, acuity related to ischemic injury, and perhaps repeat dosing over time among others, all the while ensuring complete and total patient safety. Accordingly, present efforts and goals of my research are aimed at i.) Optimizing methodologies utilized within the recent phase I clinical trial (SCIPIO) that showed intracoronary infusion of 1 million c-kit positive cardiac progenitor cells was safe with indications of efficacy in cardiac repair, as well as, ii.) Development of a novel cell based approach with a newly discovered cardiac cell type. Within the present dissertation, I explored the impact of coronary stop-flow on cardiac retention of intracoronarily infused c-kit positive cardiac progenitor cells given that balloon inflation in a non-stented coronary artery is inherently dangerous, especially in already damaged hearts. I demonstrate that intracardiac retention with or without stop-flow is equivalent and balloon inflation confers an undue risk to patients. Furthermore, I investigated the safety of intracoronary infusion of 20 million c-kit positive cardiac progenitor cells in pigs, an equivalent dose 40 times larger than was used in the SCIPIO trial. High dose of cells delivered intracoronarily is safe and does not result in myocardial injury or functional deficit. Therefore, larger doses may reasonably be utilized in future clinical trials. Finally, I describe a novel adult cardiac cell type that maintains expression of an embryonic stem cell associated marker, stage-specific embryonic antigen (SSEA)-3, resides within the native adult heart, and can be isolated and utilized for cardiac repair as a cell based therapy.
Keith, Matthew C. L., "Cell-based therapies for ischemic cardiomyopathy : investigations of intramyocardial retention and safety of high dose intracoronary delivery of c-kit positive cardiac progenitor cells, and therapeutic utility of a novel population of cardiac mesenchymal stem cells expressing stage-specific embryonic antigen-3 (SSEA-3)." (2016). Electronic Theses and Dissertations. Paper 2390.