Public Abstract:
A major goal of the stem cell research is to regenerate the damaged human tissue by creating physiologically relevant cell types. Human stem cells and induced pluripotent stem cells provide us a promising source for the cardiomyocytes. Recent technological advances have made possible the transplantation of these cells and generation of biological cardiac sheet which could supplement the contractility of the failing heart. While researches towards the application of the stem cells are advancing rapidly, however, initial clinical trials suggest that their cardiac regeneration potential is controversial and that the functional benefits are modest. Further understanding of the basic biology of human cardiac differentiation is required before designing larger-scale trials.
Although recent progress in animal models has revealed the diversity of cardiovascular cell populations, we are at a relatively primitive stage in understanding how immature human stem cells give rise to diverse cell types in human cardiovascular system including atrial and ventricular myocardium, cardiac pacemaker cells, and the smooth muscle and endothelial cells in the vasculature. This project will elucidate the basic mechanism of cardiovascular cell diversification with the goal of future cell replacement therapy for regenerating the heart.
Our international research team comprise of medical scientists who have gained fundamental insight into cardiac differentiation from animal models, and researchers who have developed new technologies in genetically manipulating human stem cells. Combination of the expertise will enable us to analyze the basic cellular and molecular mechanism underlying the diversification of human cardiac populations at unprecedented resolution. Knowledge from this proposal will help understand disease mechanisms of congenital and adult heart diseases, and develop stem cell-based therapy for these diseases.
Statement of Benefit to California:
Heart disease and stroke are the first and the third leading causes of death in California and a major cause of disability. 40,000 Californians are admitted to hospitals because of heart attack, and 73,000 Californians die from heart disease and stroke each year, more than the total number of deaths in that year from cancer, diabetes, chronic liver disease/cirrhosis, suicide, homicide, and AIDS combined. Additionally, cardiovascular diseases impose an enormous economic burden on our State. The annual cost for heart disease and stroke is $300 billion to the U.S. and $48 billion to California alone. The cost will gradually increase because the number of deaths from cardiovascular diseases will undoubtedly increase as the State’s population ages. It is clear that novel therapeutic approaches are needed to halt the devastating consequences of heart disease and stroke. Stem cell-based regenerative technologies proposed in this study in partnership with international collaborators will provide a platform for the analysis of the mechanism of cardiac regeneration and a promise to repair the damaged myocardium. Now the whole stem cell research is progressing rapidly in the world, the exchange of information and organized activities of fundamental researches are becoming more and more important. The opportunity to bring in new ideas and essential technologies will help both Californian and Japanese scientific communities further expand and strengthen the stem cell research.
Review Summary:
EXECUTIVE SUMMARY
The goal of this proposal is to understand basic mechanisms of heart development using human embryonic stem cells (hESCs). The applicant proposes three Specific Aims. In Aim 1, the applicant will generate hESC reporter cell lines that will allow the isolation, culture and characterization of cardiovascular progenitor populations. In Aim 2, the applicant proposes to determine the gene expression profiles and differentiation potentials of these progenitors. In Aim 3, the applicant proposes to investigate the molecular mechanisms of cardiovascular progenitor differentiation into smooth muscle.
Reviewers agreed that this proposal addresses significant questions in stem cell biology and regenerative medicine. While much has been learned from mouse studies of cardiogenesis, the longer onset of heart cell lineage diversification and expansion in humans suggests divergent pathways. Greater understanding of human cardiovascular progenitor cell relationships and developmental stages could ultimately translate into novel approaches for cell-based therapies for cardiac disease. Reviewers did not find the proposal particularly novel or innovative as many groups are generating knock in reporter hESC lines to study lineage-specific differentiation. However, they noted that the proposed methods may be uniquely suited to achieve this goal.
Reviewers described the research plan as logical and well organized, but overly ambitious. A major weakness they cited is the dependence of the proposed research on the generation of numerous hESC lines genetically modified by homologous recombination, including one line with a double knock in. None of the proposed lines have yet been produced. This limitation caused the reviewers to question whether the proposed experiments could be completed in three years. In addition, they noted that the preliminary data mostly represent mouse studies and that the very limited hESC preliminary data are not compelling. Reviewers also felt that aspects of the research plan were lacking essential detail. For example, it was unclear how studies involving characterization of cardiomyocytes at specific time points during differentiation would be performed.
Reviewers described the principal investigator (PI) as a junior investigator with a modest publication record. They were concerned by his/her limited experience working with hESCs, although they noted that the Partner PI has a great deal of expertise in this area, including expertise with homologous recombination in hESC. Reviewers were also not convinced that the PI’s track record demonstrates the ability to manage an international collaboration of this kind.
Overall, while reviewers appreciated the significance of this proposal, they raised doubts about the experience of the PI and the project’s feasibility, given the ambitious nature of the research plan.
