Electrical Maturation and Integration of Human Pluripotent Stem Cell-Derived Cardiomyocytes
Pathology, University of Washington
January 29, 2015
Foege N130A, Wallace H. Coulter Seminar Room
Human pluripotent stem cells have a number of potential advantages for use in cardiac repair, including tremendous capacity for expansion and unambiguous cardiac potential. Our group has shown that the transplantation of human embryonic stem cell (hESC)-derived cardiomyocytes in animal models of myocardial infarction promotes the partial remuscularization of the infarct scar and mediates improvements in left ventricular contractile function. However, a number of important challenges remain, including concerns about the immature and heterogeneous electrophysiological phenotype of hESC-derived cardiomyocytes, the ability of these cells to undergo appropriate electromechanical integration following transplantation, and the risk of graft-related arrhythmogenesis. In this presentation, I will highlight our group’s recent progress on each of these issues. First, we have developed improved protocols to promote the structural and functional maturation of hESC-derived cardiomyocytes in vitro. In related work, we have pursued multiple approaches to obtain enriched populations of specific cardiac subtypes from hESCs (e.g. nodal/pacemaker versus ventricular myocytes), including genetic selection with subtype-specific promoters and pharmacological manipulation. Finally, we have developed new optical mapping techniques to examine the electrical behavior of hESC-derived cardiac grafts in injured hearts and to study the dynamic interactions between host and graft tissue under baseline and stressed conditions. Currently, we are applying these tools to explore a variety of complementary strategies to enhance the electrical stability of engrafted hearts. Taken collectively, these advances bring us closer to the goal of replacing infarct scar with electrically coupled and phenotypically mature stem cell-derived myocardium.
Dr. Laflamme is an Associate Professor of Pathology at the University of Washington, where he leads the cardiovascular pathology subspecialty service and conducts research in cardiac stem cell biology. After earning his bachelor’s degree from Georgetown University, he completed the Medical Scientist (M.D./Ph.D) Training Program at Emory University. Dr. Laflamme then came to the UW for residency training in Anatomic Pathology, followed by subspecialty training in cardiovascular pathology and a postdoctoral fellowship in stem cell biology. He has been faculty at the UW since 2004, where he provides diagnostic information on cardiovascular-related surgical specimens (e.g. heart transplant biopsies, diseased valves, etc.) and leads an NIH-funded laboratory that is focused on developing novel stem cell-based therapies for heart disease. His lab is broadly interested in the differentiation and use of cardiomyocytes derived from human pluripotent stem cells with a particular emphasis on their electrophysiological behavior both in vitro and in vivo. Dr. Laflamme has been the recipient of honors including the Society for Cardiovascular Pathology Young Investigator Award, the American Heart Association Basic Sciences Poster Prize, the Perkins Coie Award for Discovery and the American Society of Gene & Cell Therapy Outstanding New Investigator Award.