Full text release has been delayed at the author’s request until May 20, 2013.

Degree

Doctor of Philosophy, Case Western Reserve University, Cell Biology, 2012.

Abstract

Cardiovascular disease is the leading cause of death in the industrialized world and its prevalence is increasing worldwide. Regenerative medicine represents a new medical frontier for the treatment of heart failure. This therapeutic approach has mainly focused on the delivery of exogenous stem cells. While clinical trials have shown no major safety concerns, the outcomes associated with the use of exogenous stem cells have shown some degree of efficacy in selected cases. In addition to exogenous stem cells, endogenous populations of stem cells exist and can be activated to promote tissue healing. However, the exact role of endogenous stem cells in cardiac regeneration is far from clear.

In Chapter Three, we examined the response of endogenous stem cells to trans-aortic constriction (TAC) in a mouse model. Our results demonstrated an early, orchestrated systemic response of cardiac stem cells (CSC), endothelial progenitor cells (EPC), and SSEA1+ stem cells following TAC. The most significant response found was in the splenic and bone marrow EPC and SSEA1+ populations. These cells showed early mobilization and accumulation in the heart, prior to any proliferative response. Peak stem cell content in the myocardium occurred at 7 days post-TAC. These data identify stem cell sources and populations respondent to TAC.

Chapter Four focuses on bone marrow SSEA1+ cells. Through chimeric bone marrow studies, we found that SSEA1+ cells can differentiate into other cells types, including hematopoietic stem cells, EPC, and endothelial cells. We also determined that bone marrow SSEA1+ cell support is essential in maintaining cardiac homeostasis after TAC. Depletion of bone marrow SSEA1+ cells quickened cardiac dysfunction and increased vessel rarefaction after TAC. These results have begun to define the fate and function of bone marrow SSEA1+ cells. The data presented in this dissertation demonstrate a strong support of the myocardium by peripheral stem cells. The next generation of stem cell therapies may focus on manipulating the endogenous peripheral stem cells as well as the local CSC.

Subject Headings

Cellular Biology

Keywords

endogenous stem cell; cardiac pressure overload; SSEA1+ cells; endothelial progenitor cells

Committee / Advisors

Paul DiCorleto, PhD (Advisor)
Marc Penn, MD PhD (Advisor)
Piet de Boer, PhD (Committee Chair)
Horst von Recum, PhD (Committee Member)

Pages

155p.

Document number: case1333897602
Permalink: http://rave.ohiolink.edu/etdc/view?acc_num=case1333897602