Mechanisms of Cardiomyocyte Maturation
Stem cell-derived cardiomyocytes are promising for numerous in vitro and in vivo applications. Clinical applications include use in transplantation studies to treat heart disease, which remains a major cause of morbidity and mortality in developed countries despite advances in therapy. There are numerous applied and basic research applications, including their use directly in transplantation, their use in assays to discover drugs to treat heart disease, and the in vitro testing of drug candidates for adverse effects on cardiac physiology. Realization of the potential of stem cell-derived cardiomyocytes for these important applications is hampered by the electrical and mechanical immaturity of the cells. Immaturity makes them poor models of adult cardiomyocytes and poorly functioning in in vivo applications.
Currently, it is not possible to direct functional maturation since the signals and genes that drive the process are largely unknown. Data are presented in this application showing the development of instrumentation and software for high throughput assessment of electrophysiological maturation. We also show, using this technology, that electrical and ion channel profile maturation of human embryonic stem cell and human induced pluripotent stem cell (hESC- and hiPSC)-derived cardiomyocytes can be driven by paracrine signaling from vascular endothelial cells and by Kruppel-like factors (KLFs) within the differentiating myocytes.
The goal of this project is to identify and characterize the factors and genes that direct cardiomyocyte maturation. The findings will constitute a conceptual advance since little is known about the regulation of physiological maturation, and it will be highly significant for basic and applied research and regenerative medicine since it will enable the production of mature cardiomyocytes from hESCs/hiPSCs, and potentially from endogenous cardiac stem cells in vivo, thereby increasing the value of stem cell cardiogenesis for medical applications.
This proposal is a multidisciplinary collaboration among stem cell biologists and engineers to address a critical problem that limits the widespread use of stem cells (in particular hESCs and hiPSCs) for cardiology. Developing the multidisciplinary technology and overcoming the hurdles to application of stem cells will benefit California in many ways, including:
1. Research to discover novel tools to stimulate heart muscle regeneration from is clinically important. Cardiovascular disease is the single largest cause of death in the U.S. and the assays we will develop and the reagents themselves will be useful tools to direct cardiomyocyte regeneration. This will speed the translation of hESCs to the clinic, specifically by stimulating production of cardiomyocytes and potentially by enhancing their integration and function after engraftment.
2. Heart regeneration from stem cells probably uses similar cellular proteins and signaling pathways as regeneration of cardiomyocytes from endogenous sources, thus, this research might lead to drugs that enhance natural repair of the heart.
3. Bringing the diverse people together (cell biologists and engineers) to address a stem cell problem forges new links in the academic community that should be capable of opening new areas of research. These new areas of research will be an important legacy of CIRM and promises to invigorate academic research.
4. Lastly, supporting the leading edge technology and the collaboration will build the California infrastructure of high throughput chemical library screening so that it can be focused on other areas of biomedical research, both stem cell and non-stem cell.