Nearly 5 million people in the US are afflicted with heart failure with an additional 550,000 new cases diagnosed each year. Despite current treatment regimens, heart failure still remains the leading cause of morbidity and mortality in the US and developed world because of the inability to adequately replace lost ventricular myocardium from myocardial infarctions/ "heart attacks." Thus, cell-based therapies to replace lost or damaged ventricular myocardium hold great potential. In addition, potential therapies for heart failure and other cardiac diseases would also benefit from an experimental human ventricular cardiomyocyte model. Progenitor cells which can differentiate into various myocardial cell types and include human embryonic stem cells (hESCs), human induced pluripotent stem cells (hiPSCs), or adult human stem cells, can potentially address both of these therapeutic needs. Although progenitor cells can be differentiated into immature myocardial cell types, the failure to expand sufficiently and fully differentiate them into mature and functional ventricular cardiomyocytes has remained a major bottleneck in realizing the potential of human pluripotent stem cell (hPSC)-derived cardiomyocytes for human cardiac regenerative repair and in vitro modeling of adult human cardiac diseases. To overcome limiting numbers of progenitor cell derived cardiomyocytes, a major thrust of investigation has been directed toward increasing the efficiency with which a pluripotent cell adopts mature cardiomyocyte cell fates. In this proposal, we will perform complementary studies to enhance the yield of mature and functional ventricular cardiomyocytes by defining factors which promote their expansion. Additionally, we will also identify factors which promote maturation of early differentiated ventricular cardiomyocytes. Because of its great therapeutic potential, we will focus on defining microRNAs which can promote either proliferation or maturation. Toward this end, we have developed a novel system that allows us to specifically monitor in real-time hESC-derived cardiomyocytes as they proliferate and mature into functional ventricular cardiomyocytes after treatment with identified microRNAs . Overall, understanding these basic mechanisms which lead to expansion of early differentiated ventricular heart cells and their maturation will ultimately provide novel approaches towards creating a safer and more functional source of ventricular myocardial replacement for injured ventricles in heart failure patients. Additionally, although we are utilizing hESCs as our model system, it is likely that these basic mechanisms that we identify will also be applicable to cardiomyocytes derived from other potential cellular sources such as hiPSCs or other progenitor cell populations.
Statement of Benefit to California:
Nearly 5 million people in the US are afflicted with heart failure with an additional 550,000 new cases diagnosed each year. Despite current treatment regimens, heart failure still remains the leading cause of morbidity and mortality in California, US and developed world because of the inability to adequately replace lost ventricular heart cells from myocardial infarctions or "heart attacks." Thus, the goal of our experiments is to address this major roadblock by understanding the molecules that are required to instruct human stem cells to expand and become mature and functional ventricular heart cells. These studies have the real potential to not only revolutionize our understanding of creating ventricular heart cells but also provide a safer and more functional source of heart tissue replacement for the many citizens of the State of California who suffer from heart failure.