Cardiovascular disease (CVD) is the most common cause of morbidity and mortality in the US. In adults, it is most commonly caused by heart attack, which leads to reduced function of the LEFT ventricle (LV). At the same time, congenital heart disease (CHD) is the most common cause of birth defect in infants. Due to advances in infant cardiac surgery, it is now estimated >1 million adults have CHD, more than the number of children with CHD. However, many of these adult CHD patients will eventually develop dysfunction of RIGHT ventricle (RV) secondary to chronic volume overload and pulmonary hypertension (PHTN). This group of CHD patients can only be cured by heart transplantation, which is severely limited by chronic organ shortage. For our study, we will use human induced pluripotent stem (hiPS) cells reprogrammed from cells of human donors to investigate CVD and CHD. These hiPS cells will be genetically engineered to express colored flags in order to discriminate between the RV and LV progenitor cells. We will characterize the biological properties of these 2 different cell populations. We will transplant them into mouse models of MI and PHTN to demonstrate the potential of RV and LV cardiac progenitors for repair RV and LV dysfunction, respectively. Cell fate after transplantation will be carefully characterized by molecular imaging. In summary, these studies will provide valuable insights into two of the most common heart diseases affecting adults and children alike.
Statement of Benefit to California:
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the US. In adults, it is most commonly caused by heart attacks causing reduced function of LEFT ventricle (LV). Congenital heart disease (CHD) is the most common cause of birth defect in infants. Due to advances in infant cardiac surgery, the number of pediatric and adult patients with congenital heart diseases has reached 1.8 million in the US and growing. Many of these CHD patients will eventually develop dysfunction of RIGHT ventricle (RV) secondary to chronic volume overload and pulmonary hypertension later in life. Hence there is an urgent need to generate new strategies such as stem cell therapy for these patients. Our proposal to engineer specific RV and LV cardiac cells from human pluripotent stem (hiPS) cells is highly relevant to the main goals of CIRM, one of which is to explore the therapeutic potential of hiPS cells in degenerative diseases. We further intend to deeply characterize at a genetic and epigenetic level the cells that we will transplant in animal models of RV or LV dysfunction, thus fulfilling the safety expectations of the CIRM in cell therapy. We believe the outcome of our project will have high clinical and basic science value in enabling a better understanding of cardiac developmental biology and a better cell therapy approach for both CVD and CHD, thus significantly benefiting the citizens of California.