Cardiovascular disease is the leading cause of death and disability in the United States. Cell transplantation using the patients’ own cells (autologous cells) to repair the heart is a promising new approach with the potential to treat the millions of patients with debilitating heart conditions. Current therapies do not restore the function of the scarred area after myocardial infarct. Through stem cell research, it has been shown that the heart itself contains a repository of stem and progenitor cells that have the unique ability to give rise to cardiomyocytes, endothelial cells and vascular smooth muscle cells, all of which collectively contribute to repairing damaged heart tissue. These cells have gained considerable interest because recent studies have shown that other autologous sources, such as the bone marrow, have not been as effective as originally hoped for regeneration of the heart in early clinical trials. In order to determine the best way to harness this population of resident cells to help patients with heart disease, the methodology to reproducibly isolate and expand the cells must be developed in the laboratory and they must be shown to be both effective in the long term and safe for clinical use. Our research group is a highly interactive team of surgeons, clinicians and basic scientists who are working together to identify new ways to help both children and adults with heart disease by developing methods to use the patients’ own cells to identify new therapies that are both effective and safe. We have recently identified markers that can be used to sort the progenitor cells that are needed for cardiac repair and now propose to optimize the conditions that will allow us to expand these cells to sufficient numbers for transplantation and carefully test long term function in preclinical models.
Statement of Benefit to California:
Heart attacks are one of the leading causes of death in California. The California Office of Statewide Health Planning recently estimated that approximately 40,000 heart attack patients are admitted to California hospitals annually. These statistics are further supported by a study from the California Health Care Foundation which concluded that heart disease and hypertension (leading to heart disease and stroke) represent two of the four most common chronic health conditions in this state. Heart disease and the associated costs of treating these patients are unquestionably a significant public health challenge. The most recent estimates suggest that costs of annual health care for California residents with heart disease are about $12,900 per capita, over five times the health care costs of the general adult population. It would benefit the residents of this state, and the general population, if scientists could develop new and cost-efficient treatments for patients with heart disease. Recent advances in the field of stem cell research have led to the identification of progenitor cells that can be expanded from the patients’ own cells. Our research team of surgeons, cardiologists and basic scientists have identified a population of progenitor cells that can be isolated from autologous heart tissue and/or from re-programmed differentiated human cells. The research that we propose to do will identify new and improved ways to expand these cells for transplantation into the heart and optimize the conditions that promote cardiac regeneration in a safe and effective manner. The benefit of these proposed studies includes improved quality of life for patients and their families. Improved patient outcome will be translated into reduced costs of medical care. The technology associated with developing new methods for expansion and use of these cells, in partnership with industry, has the potential to bring new revenue to the state and to research institutions. This will enhance the opportunities for the education and training of new scientists and the recruitment of established investigators to educational centers of higher learning in the state of California.
This developmental candidate proposal focuses on utilizing autologous cardiovascular progenitor cells for myocardial repair. The investigators have identified a candidate surface marker profile to isolate a population enriched for cardiac progenitors. Two candidate cell sources expressing this marker profile will be compared for their ability to regenerate infarcted rat heart: cells isolated from pediatric cardiac biopsies and cells generated from human induced pluripotent stem cells (hiPSC). Human embryonic stem cell (hESC) derived progenitors isolated using the same marker profile will be transplanted as a control. Ventricular function and histology of these three cell treatment groups will be assessed at various times post transplant. Based on these results, a progenitor source will be selected for further study. Investigators will also screen libraries for small molecules that promote expansion or survival of autologous progenitor cells, and study the in vivo effects of these small molecules on cardiac progenitors using nanofibers as a delivery system. Finally, investigators will determine whether biopsy derived vs hESC derived cardiac progenitors achieve repair, functionally integrate, or induce arrhythmia in an animal model.
To date, heart transplant is the only curative treatment for cardiac disease, and donor hearts remain limited. Reviewers felt that this application addresses an unmet medical need, and the rationale for the use of autologous human cardiac progenitors is well described. Overall, reviewers appreciated the well written, clear research plan and the investigators’ general approach. However, the application would benefit from stronger preliminary data and further development of several sections of the research plan. The plan addresses the limitation of short-term small animal studies for the assessment of arrhythmogenesis and efficacy, and illustrates the need for large animal models, in which the PI has expertise. Preliminary data in the proposed animal model and further description of how arrhythmia will be monitored therein (e.g., spontaneous or induced) would strengthen the proposal. Action potential studies, gap junction studies, and the chemical library screen to identify factors that promote expansion of cardiac progenitors and metrics for success should be further described. Reviewers noted some conceptual issues regarding the cell populations selected for study. The pediatric cardiac biopsies encompass multiple tissues that may require incompatible disaggregation and preparation procedures. Also, potential differences between adult and pediatric stem cell populations are not addressed and could limit the utility of results obtained with this material. Evidence that marker positive cells are enriched for cardiac progenitors appear preliminary; investigators provided limited data in the feasibility section and have not yet published this work. Given the variable cardiomyogenic potential between hESC lines, investigators should study multiple hESC lines rather than a single line as proposed. Finally, a discussion of how the data from the specific aims would be integrated towards a translational end was warranted. This team has several good co-investigators and the expertise necessary to complete all of the proposed studies. However, multiple investigators are expected to provide significant percent effort without salary support and the budget is not adequately justified. The group should have access to the required reagents and biopsies and the research environment is excellent. Concern was expressed that the PI has not yet demonstrated the ability to lead a program of this magnitude.
Overall, the proposal had good elements and received a favorable response. Human cardiac progenitors are an appropriate cell type for cardiac regeneration and better models are required for assessment of safety and efficacy. Enthusiasm was dampened by incomplete development of parts of the research plan and doubts about the junior PIs qualifications to lead such a large program.