Genetic engineering of cardiac progenitor cells for the treatment of cardiovascular disease and heart failure.

摘要

Cardiovascular disease (CVD) afflicts an estimated one in three people in the United States, accounting for more deaths annually than all other causes of death combined. The most prevalent form of CVD is coronary artery disease (CAD). CAD often leads to myocardial infarction (MI) with subsequent death of the underlying cardiac tissue. While current pharmaceutical treatments help to alleviate the increased demands placed on the damaged heart, they do nothing to regenerate and repair damaged tissue.;Recently, the use of stem cells to regenerate cardiac tissue is being explored. Unfortunately, only modest improvements in myocardial function after stem cell transplantation have been observed, raising concerns over the retention and viability of transplanted stem cells once in the damaged heart. To this end, the field of cardiac regeneration is evolving to include genetic manipulation of stem cells using cardioprotective genes to increase survival and proliferation in vivo.;Herein, we evaluate the ability of cardiac progenitor cells (CPC), genetically modified with the known cardioprotective genes, nuclear-targeted Akt or Pim-1, to improve cardiac structure and function after infarction in mice. The results presented in this thesis demonstrate CPCs modified with either nuclear Akt or Pim-1 significantly enhance proliferation in vitro and in vivo. However, overexpression of nuclear Akt in CPCs abrogates lineage commitment. Lack of terminal differentiation resulted in a lack of significant functional and structural improvements in the hearts of mice receiving injections after MI. In contrast, CPCs modified with Pim-1 kinase exhibited lineage commitment in vitro and in vivo. Mice receiving Pim-1 modified CPCs after infarction, therefore, had significant improvements in cardiac function and regeneration, compared to mice receiving unmodified CPCs. Preliminary studies indicate cellular localization of Pim-1 kinase may contribute to its ability to regulate stem cell proliferation and survival.;Taken together, this study demonstrates that CPC commitment is an essential component of the regenerative response. For cardiac stem cell therapies to be effective, cellular survival and proliferation must be promoted without inhibiting lineage commitment.