Congestive heart failure afflicts 4.8 million people, with 400,000 new cases each year. Myocardial infarction (MI), also known as a "heart attack", leads to a loss of cardiac tissue and impairment of left ventricular function. Because the heart does not contain a significant number of multiplying stem, precursor, or reserve cells, it is unable to effectively heal itself after injury and the heart tissue eventually becomes scar tissue. The subsequent changes in the workload of the heart may, if the scar is large enough, deteriorate further leading to congestive heart failure. Many stem cell strategies are being explored for the regeneration of heart tissue, however; full cardiac tissue repair will only become possible when two critical areas of tissue regeneration are addressed: 1) the generation of a sustainable, purified source of functional cardiac progenitors and 2) employment of cell delivery methods leading to functional integration with host tissue. This proposal will explore both of these 2 critical areas towards the development of a living cardiac patch material that will enable the regeneration of scarred hearts.
The research proposed in expected to result in new techniques and methodology for the differentiation of stem cell-derived cardiomyocytes and delivery methods optimal for therapeutic repair of scarred heart tissue after a heart attack. The citizens of California could benefit from this research in three ways. The most significant impact would be in the potential potential for new medical therapies to treat a large medical problem. The second benefit is in the potential for these technologies to bring new usiness ventures to the state of California. The third benefit is the stem cell training of the students and postdocs involved in this study.
This project proposes to produce a viable cardiac tissue patch for heart failure applications. This patch will be biocompatible, non-arrhythmogenic, and derived from human embryonic stem cells (hESC’s). Many stem cell strategies are being explored for the regeneration of heart tissue; however, full cardiac tissue repair will only become possible when a sustainable, purified source of cardiac progenitors is generated and when functional integration can be achieved within the host tissue. The applicant proposes to achieve this by constructing and testing a tissue patch made up of hESC-derived cardiomyocytes seeded into an acellular natural scaffold.
Reviewers highlighted the clinical significance of the problem, and identified novel aspects of the proposal as key strengths of the application. These novel features included the focus on a combined cardiomyocyte and endothelial cell approach, a differentiation strategy combining biochemical and electrical stimulation, and the use of bioscaffolds as delivery vehicles. The investigator has experience in the differentiation of cardiomyocytes, in studying their electromechanical properties, and in the construction of acellular matrices. Furthermore, the applicant has experience with a swine model of myocardial infarction, which may serve as a more accurate model of human physiology than do rodent systems. Appropriate collaborators are in place.
Despite these strengths, reviewers had some minor concerns with the research proposal. Differentiation protocols lacked adequate detail, and it was not clear that the proposed experiments would result in enriched populations of cardiomyocytes. One reviewer noted that the experiments were dependent upon a laboratory tool yet to be developed (the subject of another grant), and no preliminary data was included in the application to address progress of this development. If the tool fails to become available, the proposed project becomes one of very basic characterization. Finally, reviewers commented that the inclusion of data showing that the matrices can be successfully seeded with cells would have strengthened confidence that proposed aims can be achieved.
Reviewers acknowledged the significant strengths of the applicant. The Principal Investigator (PI) has several publications on the specification of endothelial cells from ESCs. The PI is the Chair of a graduate program of bioengineering and small-scale technology. Career development goals are clearly articulated. Long-range research goals include translating the work the applicant has performed in murine ESCs to human platforms and refining tissue engineering strategies. A panel of mentors with good expertise has been assembled, although the mentoring plan lacks detail.
The institutional support was judged to be very substantial, as reflected in a strong letter of support from the Dean. The institution is fostering development of an emerging stem cell and tissue engineering program, and several additional researchers in these areas have been recruited in recent years. The PI’s startup package was judged to be ample and included laboratory space, and financial and administrative support.
A motion was made to recommend this application be moved to Tier 1 - Recommended for Funding. The panel concurred that the applicant is in a leadership position at the institution and has key responsibilities with the stem cell facility and oversight of the program. This award would accelerate the applicant’s career and would help the PI gain expertise in the field of stem cell-derived cardiomyocyte biology. Although the panel acknowledged a few pitfalls in the research plan, they felt that this weakness was offset by an insightful, clearly articulated hypothesis and a particularly innovative proposal. The motion to move this application to Tier 1 carried.