A Mechanism-guided Chemical Biology Approach to iPSC-derived Cardiomyocyte Death

Abstract:

Cell therapy holds great promise for a variety of cardiac syndromes. While some human studies have been encouraging, the improvements have been modest. A major impediment to therapies based on the delivery of exogenous cells is that more than 90% of these cells die in the first 24 hours. The loss of these cells dramatically limits therapeutic efficacy. While the importance of this problem is widely acknowledged, its underlying mechanisms are not well understood, and significant progress toward effective and clinically practical solutions is lagging. The objectives of this application are to delineate the death pathways responsible for the loss of transplanted cells during cardiac cell therapy and to develop small molecule approaches to prevent, inhibit, or delay the deaths of these cells. Even a delay in cell death might provide the time necessary for successful engraftment. Cell death signaling is complex involving more than one death process and multiple interconnected core pathways. For the past 20 years, the laboratory of the PI has focused on fundamental mechanisms of cell death and their roles in the pathogenesis of disease, including acute myocardial infarction and heart failure. The system chosen for the investigations in this application is human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) because the autologous transplantation of these cells is a particularly attractive potential approach to cardiac cell therapy. The proposed studies will (a) provide the first systematic dissection of death pathways in any cell type employed in cardiac cell therapy and (b) employ chemical biology to move directly to a consideration of small molecule solutions to inhibit the massive loss of exogenously administered cells. These issues will be addressed through the following specific aims: Aim 1. To delineate the pathways responsible for the deaths of hiPSC-CM in response to death stimuli that operate during myocardial delivery. Aim 2. To test small molecules, previously identified by the PI in a large high-throughput cardioprotection screen, for their effectiveness in inhibiting hiPSC-CM death, and to delineate the death pathways they inhibit. Aim 3. To assess the efficacy of selected small molecules in promoting the survival of hiPSC-CM and lessening cardiac dysfunction in a post-infarct model in vivo. This application brings together a lab that has been at the forefront of cardiac cell death with a team that possesses great expertise in hiPSC-CM biology and which has unparalleled accomplishments in cardiac cell imaging (critical to these studies) to address a major gap in knowledge that has stalled the effective deployment of cardiac cell therapy.