University of Washington

Dr. Charles E. Murry
Induction of Cardiac Differentiation from IPS Cells
Funding granted: $37,500
Summary of Research: Induction of Cardiac Differentiation from IPS Cells Provided by Dr. Charles E. Murry, University of Washington

The formation of a fully functional heart requires a complex series of developmental events that begin very early during embryonic life. The early heart forms a tube that loops in a sequential pattern that leads to the formation of four chambers. During the maturation process a vascular network develops, creating a system for pumping blood throughout the body. Disturbances in this finely tuned developmental pattern leads to congenital heart defects, which affect thousands of newborns every year. Although cardiac muscle cells divide robustly during the early stages of development, as the heart matures, they loose the capacity to proliferate. Thus, to date, people that have sub-optimal amounts of cardiac muscle cells due to congenital defects or injury have a permanently impaired cardiovascular function. Because of the great promise that cell-based therapies have to improve the quality of life for patients with heart disease, our laboratory is focusing on this exciting new approach to address this problem.

One of the goals of our laboratory is to supply damaged hearts with cardiovascular cells that will improve function. Many adult cells have been examined as potential sources to obtain cardiac muscle cells, but none have been shown to generate these cells at therapeutically relevant levels. This is not surprising in light of the fact that although in the earliest stages of development, embryonic cells are pluripotent (they have the capacity to become any cell type in the body), as the embryo matures, cells become restricted and functionally specialized. Some organs like the liver retain a remarkable regenerative capacity; however, the human heart is not naturally capable of repairing cardiac muscle deficiencies. To date, embryonic pluripotent stem cells (ES) have been shown to be the most reliable sources of cardiac muscle cells. The utilization of ES derived cardiac muscle cells for human therapy will require a large amount of input cells. Towards this goal, we have established a method that generates cardiomyocytes from human ES cells at a higher efficiency than previously established methods. We recently used this method to generate cells that were transplanted into infarcted rat hearts. Our studies showed an improvement in cardiac function.

In addition to the advances in ES cell technology, recent breakthroughs have led to the generation of human induced pluripotent stem (iPS) cells (non-embryonic cells that have been reprogrammed to a developmentally immature state). We believe that iPS cells are promising because the reprogramming method allows them to regain the ability to become multiple different cell types, including cardiac muscle cells. These cells also present the opportunity to generate patient-specific cells that could bypass the challenges of immune rejection. Our research will focus on experiments that aim to optimize the yield of cardiac muscle cells derived from human iPS cells.