Cardiovascular diseases remain the leading cause of death worldwide, but three innovative projects underway at the University of Wisconsin–Madison are helping to change that. Led by Stem Cell and Regenerative Medicine Center (SCRMC) investigators and supported by a gift from the Wisconsin Alumni Research Foundation (WARF), these projects will explore the development of improved stem cell models, equipment, and increase understanding of disease mechanisms.
More specifically, one project will seek to develop cardiomyocytes, heart muscle cells, from porcine induced Pluripotent Stem Cells (PiPSCs). Often known as the body’s master cells, iPSCs are living donor cells that are reprogrammed into embryonic-like pluripotent cells. Since pigs share similar size, anatomy, physiology, and immunology with humans, they have emerged as the preferred translational model for studying therapies prior to clinical use. While it is believed that the development of cardiomyocytes from PiPSCs holds tremendous potential to advance cardio-regenerative medicine, there is not currently a line of characterized PiPSCs derived cardiomyocytes (PiPSC-CM) available as a campus resource. This project would seek to change that.
“The Stem Cell Regenerative Medicine Cardiovascular pilot award is crucial in advancing the development of Porcine induced Pluripotent-derived cardiomyocytes,” says Eric Schmuck, the principal investigator on this project and the School of Medicine and Public Health research operations director. “With this support, we can leverage the unique properties of swine models to address critical mechanistic and translational research questions. This funding enables us to pave the way for innovative therapies that could transform the treatment of cardiovascular disease.”
Another project will also provide new campus resources by securing a high-quality vibrating microtome to prepare viable porcine myocardial slices. Myocardial tissue, which is the muscular layer of the heart wall, has limited regenerative capacity and when damaged during events such as myocardial infarction, results in loss of functional heart muscle. One way to combat this loss is to remuscularize the injured heart by delivering human pluripotent stem
cell-derived cardiomyocytes. While nonhuman models suggest this could be a viable option, a side effect is often tachycardia, or a rapid heart rate, that can be life-threatening. This barrier has been a hinderance to clinical adaptation, but new research suggests a method involving the use of a vibrating microtome to gather cardiac slices that are then maintained in culture for a week or more may result in less risk of tachycardia. This funding will provide the vibrating microtome needed to continue this critical research being led by Cardiovascular Medicine Associate Professor Alexey Glukhov, PhD, MS.
Additionally, senior scientist Jianhua Zhang, PhD will be investigating the mechanisms behind Brugada syndrome (BrS), an inherited arrhythmogenic (abnormal heart rhythm) disease associated with sudden cardiac death and the leading cause of cardiac death in those under 40. Zhang hopes to develop a panel of patient-independent iPSCs that carry the BrS mutations and can therefore be used to investigate the mechanisms behind this disease. The cell line can also be used to test potential therapies, including tRNA therapeutic strategies.
“We are excited to use this award to generate CRISPR/Cas9 gene-edited, patient-independent iPSC lines and chamber-specific iPSC-cardiomyocytes to enable studies of the pathogenesis of Brugada Syndrome,” says Zhang. “Even more exciting will be our ability to test novel engineered tRNA therapies for Brugada Syndrome using these lines. This pilot award will form the foundation of a collaborative multiple PI R01 application.”