Because the regenerative capacity of adult heart is limited, any substantial cell loss as a result of a heart attack is mostly irreversible and may lead to progressive heart failure. Human pluripotent stem cells can be differentiated to heart cells, but their properties when transplanted into an injured heart remain unresolved. We propose to perform preclinical evaluation for transplantation of pluripotent stem cell-derived cardiac cells into the injured heart of an appropriate animal model. However, an important issue that has limited the progress to clinical use is their fate upon transplantation; that is whether they are capable of integrating into their new environment or they will function in isolation at their own pace. As an analogy, the performance of a symphony can go into chaos if one member plays in isolation from all surrounding cues. Therefore, it is important to determine if the transplanted cells can beat in harmony with the rest of the heart and if these cells will provide functional benefit to the injured heart. We plan to isolate cardiac cells derived from human pluripotent stem cells, transplant them into the model’s injured heart, determine if they result in improvement of the heart function, and perform detailed electrophysiology studies to determine their integration into the host tissue. The success of the proposed project will set the platform for future clinical trails of stem cell therapy for heart disease.
Heart disease remains the leading cause of mortality and morbidity in the US with an estimated annual cost of over $300 billion. In California alone, more than 70,000 people die every year from cardiovascular diseases. Despite major advancement in treatments for patients with heart failure, which is mainly due to cellular loss upon myocardial injury, the mortality rate remains high. Human embryonic stem cells (hESC) and induced pluripotent stem cells (iPSC) could provide an attractive therapeutic option to treat patients with damaged heart. We propose to isolate heart cells from hESCs and transplant them in an injured animal model's heart and study their fate. In the process, we will develop reagents that can be highly valuable for future research and clinical studies. The reagents generated in these studies can be patented forming an intellectual property portfolio shared by the state and the institution where the research is carried out. Most importantly, the research that is proposed in this application could lead to future stem cell-based therapies that would restore heart function after a heart attack. We expect that California hospitals and health care entities will be first in line for trials and therapies. Thus, California will benefit economically and it will help advance novel medical care.
This proposal aims to identify the best cardiovascular progenitor (CVP) to repair injured hearts. The applicant plans to achieve this by testing CVP of varying maturities for their ability to improve function in a relevant preclinical heart attack model. First, a series of sorting and proteomics studies will be performed to enable identification and isolation of specific CVP developmental stages. Autologous induced pluripotent stem cell (iPSC) derived CVP isolated at various stages will then be transplanted into the relevant preclinical model, and assessed for their ability to integrate into the host heart and improve cardiac function. A similar transplant study will then be performed using human embryonic stem cell (hESC)-derived CVP.
- Reviewers praised this well written proposal for targeting several critical roadblocks to clinical translational of pluripotent stem cell derived cardiomyocytes. These include: identification of the most appropriate cell, the low rates of graft:host coupling observed to date and establishment of efficacy data in relevant preclinical models. They felt the program would make an important contribution to the field.
- The panel expressed universal enthusiasm for the applicant’s novel autologous transplantation approach and use of state of the art analysis techniques in the relevant preclinical model. They noted that reports of this type of study are lacking in the field, and that this work could reveal the limitations of iPSC derived cardiac cells.
- While the panel was intrigued by the proteomics work and felt it would be informative, this element of the proposal was not especially translational. They noted some markers of human cardiac progenitors have already been identified, and suggested testing the utility of these prior to initiating a full-blown proteomics screen.
- While preliminary data support feasibility of much of the proposed studies, reviewers would have appreciated preliminary data utilizing iPSC from the preclinical model, given the reported challenges culturing and differentiating existing lines of this type.
- The PI has excellent interdisciplinary background with training in cardiology, stem cell biology and surgery in the proposed preclinical model. S/he has demonstrated commitment to the proposed field of study and possesses a strong publication record relevant to the proposed program.
- The panel found both the mentoring team and plan outstanding. They did note the mentors’ track records did not appear to be in the hESC-derived CVP field; however, this expertise can readily be found in the host institution environment.
- The institution has an exceptional track record for promoting young physician scientists and is committed to translation of stem cell research. Further, the institution’s strong commitment to the applicant includes protected research time, laboratory space and a start up package.
- Reviewers praised the proposal as an excellent fit for the RFA. Its use of human pluripotent stem cells and translational goal to identify a therapeutic candidate render it highly responsive.