Cell-based cardiac repair

Abstract

Myocardial infarction (MI) is the leading cause of death in the western world. After occlusion of a coronary artery, many cardiomyocytes are damaged and replaced by a thick fibrous scar. This leads to a decline in cardiac function, and will inevitably cause death due to heart failure. Although the treatment of MI has improved dramatically over the last decades, none of the current therapies deal with the underlying cause, which is the loss of cardiomyocytes. Since the surviving cardiomyocytes cannot divide, the heart is unable to restore itself. Therefore attention turned to the possibility of cell-based cardiac repair. In this thesis several aspects of cell-based therapy are investigated. The idea behind cell-therapy is that stem or progenitor cells will be delivered to the damaged tissue, where they locally form new heart tissue. We have recently identified a population of cardiomyocyte progenitor cells (CMPCs) that is present in the fetal and adult heart. These CMPCs can form both spontaneously beating cardiomyocytes and vessel-like structures in vitro. Therefore they represent a very interesting candidate for cell-based therapy. The ability of CMPCs to repair the infarcted heart was investigated. In a mouse model for MI, CMPCs were injected into the borderzone of the infarct. During three months, heart function was measured by MRI. This analysis showed that injection of these cells prevented the deterioration of cardiac function. Interestingly, the CMPCs differentiated in vivo into new cardiomyocytes, as well as vessel-like structures. Although CMPCs were able to partially repair the heart, only small foci of new tissue were formed. In an attempt to increase the number of transplanted cells that remain in the heart, another delivery method was tested. While previously cells were directly transplanted into the infarcted heart, we chose to inject the cells into the bloodstream of the MI-mouse. CMPCs now have to home from the blood to the damaged area. As a result of the infarct, the heart produces cytokines that serve as homing signals to attract cells from the bloodstream. We showed that CMPCs carry the right tools to respond to the homing signals from the injured heart, but they cannot react adequately due to high surface levels of CD26, a migration inhibiting peptidase. We hypothesize that removing this peptidase from CMPCs may enhance their homing from the circulation to the damaged heart. This can lead to more cells in the infarcted area which may further improve cardiac function. This approach needs to be investigated further. Another option for cardiac therapy is to increase the number of progenitor cells that is present in the heart. At the moment it remains unclear what the biological function of endogenous CMPCs in the heart is. Apparently, they are unable to efficiently participate in the restoration of the damaged myocardium. To investigate the progenitor cells locally, we have generated new transgenic mouse models. Understanding the behavior of the progenitor cells after MI may lead to new methods to stimulate this population which may ultimately lead to regeneration from the inside out.