Abstract 15561: A Novel Functional Model of Cardiac Hypertrophy Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Human induced pluripotent stem (iPS) cells are ideal for functional study of disease pathogenesis. Unlike models using animals and primary cell lines, iPS cells provide a unique opportunity to directly measure complex disease phenotypes of individual patients at cell-level. Here we present a model in iPS cell-derived cardiomyocytes for molecular and functional analysis of left ventricular hypertrophy (LVH), a major risk factor for cardiovascular disease. Human iCell™ Cardiomyocytes (Cellular Dynamics International, Madison WI) were plated to confluence, allowed to recover before starving for 48 hours, and stimulated with alpha (angiotensin II, endothelin-1) and beta (isoproterenol) adrenergic agonists for up to 72 hours. Cells were measured for changes in surface area, stained for immunofluorescence visualization and harvested for gene expression analysis. All three assessments revealed strong LVH phenotypes. Surface area measurements showed significant increases in stimulated iCell Cardiomyocytes for all three agonists (p=6.59E-05) compared with unstimulated controls. We also observed significant up-regulation (p=1.49E-09) of hypertrophy markers such as intermediate-early genes C-FOS and C-JUN measured by immunochemistry. Microarray expression analysis found 160 differentially expressed transcripts with at least two-fold change. Interestingly, a subset of these genes (n=34) overlapped between the three stimulants, including angiopoietin 1 (ANGPT1, implicated in early heart development) and protein phosphatase-1 and inhibitor subunit 1A (PPP1R1A, recently linked to heart failure), suggesting that our model captured hypertrophy induced via both pathological and physiological mechanisms. These data demonstrate successful establishment of a cardiac hypertrophy model in iPS cell-derived cardiomyocytes representative of the LVH phenotype. This unique model for studying myocardial function represents an important first step towards bridging the gap between clinical disease traits and relevant cellular phenotypes that are essential for understanding the molecular mechanisms underlying complex disease such as heart failure and for the eventual development of personalized drug treatments and cell-based therapies.
- © 2011 by American Heart Association, Inc.