Abstract

High Content Biology & Cardiac Regeneration: Proliferation and Multi-lineage Differentiation Screens using Cardiac Progenitor Cells

Lauren Drowley, Associate Principal Scientist, AstraZeneca

At AstraZeneca, we are taking a broad approach to cardiac regeneration, looking at multiple cell populations and endpoints of interest.  We have examined several different human cardiac cell populations in a phenotypic screen for proliferation, including primary epicardium-derived cells from patients, and Nkx2.5+ iPSC-derived cardiac progenitor cells.  These were run as medium through-put assays with the same optimized 5-10K compound set, with hits screened through human cardiac fibroblasts to remove non-specific proliferative agents. Developing and running these screens in parallel has allowed us to identify compounds that have general proliferative properties as well as novel compounds and signaling mechanisms that specifically or preferentially target one or more cell populations of interest.  We are also interested in influencing the fate decision of progenitor cells in the damaged heart to tip the balance towards cardiomyocytes and endothelial cells to aid in the repair process.  To examine this, we have developed a multi-lineage differentiation assay in a 384-well format on the Nkx2.5+ iPSC-derived cardiac progenitor cells. Using this assay, we have screened a small compound library and have identified Wnt and MAPK inhibitors, which have a positive regulatory role in cardiomyogenic differentiation from the progenitor cell population. In addition, we have identified compounds that have not been previously described in the literature as positive regulators of cardiomyogenic differentiation.    The identification of compounds that preferentially target specific cell populations within the myocardium has allowed us to develop potential therapies that can address multiple aspects of myocardial disease and in turn have the potential to result in true cardiac regeneration.