Disease Modeling and Phenotypic Drug Screening for Diabetic Cardiomyopathy using Human Induced Pluripotent Stem Cells

• DOI: 10.1016/j.celrep.2014.09.055
• Publication Date: 2014-10-30T17:01:32Z
• Authors: Faye M. Drawnel; Stefano Boccardo; Michael Prummer; Frédéric Delobel; Alexandra Graff; Michael Weber; Régine Gérard; Laura Badi; Tony Kam-Thong; Lei Bu; Xin Jiang; Jean-Christophe H...; Anna Kiialainen; Elena Jeworutzki; Natsuyo Aoyama; Coby Carlson; Mark Burcin; Gianni Gromo; Markus Boehringer; Henning Stahlberg; Benjamin J. Hall; Maria Chiara Magnone; Kyle Kolaja; Kenneth R. Chien; Jacques Bailly; Roberto Iacone
• Keywords: Sarcomeres; 0301 basic medicine; QH301-705.5; Diabetic Cardiomyopathies; Induced Pluripotent Stem Cells; Drug Evaluation, Preclinical; Cell Differentiation; Hypertrophy; Lipid Metabolism; Models, Biological; 3. Good health; Small Molecule Libraries; 03 medical and health sciences; Phenotype; Humans; Myocytes, Cardiac; Lipid Peroxidation; Biology (General)

Diabetic cardiomyopathy is a complication of type 2 diabetes, with known contributions of lifestyle and genetics. We develop environmentally and genetically driven in vitro models of the condition using human-induced-pluripotent-stem-cell-derived cardiomyocytes. First, we mimic diabetic clinical chemistry to induce a phenotypic surrogate of diabetic cardiomyopathy, observing structural and functional disarray. Next, we consider genetic effects by deriving cardiomyocytes from two diabetic patients with variable disease progression. The cardiomyopathic phenotype is recapitulated in the patient-specific cells basally, with a severity dependent on their original clinical status. These models are incorporated into successive levels of a screening platform, identifying drugs that preserve cardiomyocyte phenotype in vitro during diabetic stress. In this work, we present a patient-specific induced pluripotent stem cell (iPSC) model of a complex metabolic condition, showing the power of this technique for discovery and testing of therapeutic strategies for a disease with ever-increasing clinical significance.