One of the obstacles to pharmaceutical and clinical applications of human embryonic stem cell (hESC)-derived cardiomyocytes is insufficient purity of these cells. Our proposed research to identify a pure population of hESC-derived ventricular cardiomyocytes will provide a solution to this obstacle: 1) hESC-derived cardiomyocytes could potentially be transplanted to replace heart muscle cells lost or damaged to cardiovascular disease such as heart attack, which is the leading cause of death in the united states and other developed countries. Present cardiac differentiation protocols induce a heterogeneous population of cardiomyocytes including ventricular, nodal and atrial subtypes, which co-exist with other undefined cell lineages and/or undifferentiated cells. Transplantation of undifferentiated cells poses the risk of tumorigenisis, while a mixed population of different subtypes may cause cardiac arrhythmias. A pure population of chamber-specific cells such as ventricular cardiomyocytes will provide safer testing of in vivo cell replacement therapy. 2) A pure population of hESC-derived ventricular cardiomyocytes could be used to develop in vitro cardiac disease models, such as cardiac hypertrophy, to assist in finding relevant cures. 3) Understanding of the molecular basis for cardiac differentiation, growth and maturation by studying the development of these cells may lead to novel approaches to regenerate damaged heart tissues by in situ induction of cardiomyocyte proliferation and/or differentiation of adult cardiac progenitor cells. 4) Pure populations of hESC-derived cardiomyocytes may provide accurate prediction of pharmaceutical drug cardiac safety. Pharmaceutical agents unintended for cardiac diseases may interfere with the normal function of ion channels on heart cells, leading to increased risks of cardiac arryhthmia and sudden death. Compared to current cell models used in cardiac toxicity test such as animal heart cells, these cells bear closer resemblance to human cardiac cells and therefore may offer greater sensitivity and specificity. In summary, our proposed research will greatly facilitate the development of applications using hESC-derived cardiomyocytes..
Our research goal is to use innovative strategies to identify a pure population of hESC-derived ventricular cardiomyocytes. The state of California and its citizens will benefit from the outcomes of this research through its roles in facilitating the development of cardiac disease therapy and improving cardiac toxicity test of pharmaceutical drugs. In addition, our research will engage both interested graduate and undergraduate students and help reach out to the broad base of students in our teaching-oriented institute, who might otherwise have no direct opportunity to learn about the significance and progress of stem cell research. This is important considering that as they become a main stream work force post graduation, they may have direct or indirect influence on the government's policy in related to stem cell research on a national level.