title: Disease modeling and phenotypic drug screening for diabetic cardiomyopathy using human induced pluripotent stem cells.
abstract: 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.
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
authors.forename: Faye M
authors.initials: FM
authors.lastname: Drawnel
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Boccardo
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Prummer
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Delobel
authors.affiliation: Center for Cell Imaging and Nano Analytics, Biozentrum, Department for Biosystems Science and Engineering, University of Basel, 4058 Basel, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Graff
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Weber
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
authors.forename: Régine
authors.initials: R
authors.lastname: Gérard
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Badi
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
authors.forename: Tony
authors.initials: T
authors.lastname: Kam-Thong
authors.affiliation: The Cardiovascular Research Center, Richard B. Simches Research Center, Massachusetts General Hospital, Suite 3201, Boston, MA 02114, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Bu
authors.affiliation: The Cardiovascular Research Center, Richard B. Simches Research Center, Massachusetts General Hospital, Suite 3201, Boston, MA 02114, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Hoflack
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kiialainen
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Jeworutzki
authors.affiliation: Cellular Dynamics International, Madison, WI 53711, USA.
authors.forename: Natsuyo
authors.initials: N
authors.lastname: Aoyama
authors.affiliation: Cellular Dynamics International, Madison, WI 53711, USA.
authors.forename: Coby
authors.initials: C
authors.lastname: Carlson
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
authors.forename: Mark
authors.initials: M
authors.lastname: Burcin
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
authors.forename: Gianni
authors.initials: G
authors.lastname: Gromo
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Boehringer
authors.affiliation: Center for Cell Imaging and Nano Analytics, Biozentrum, Department for Biosystems Science and Engineering, University of Basel, 4058 Basel, Switzerland.
authors.forename: Henning
authors.initials: H
authors.lastname: Stahlberg
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Hall
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Magnone
authors.affiliation: Cellular Dynamics International, Madison, WI 53711, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Kolaja
authors.affiliation: Departments of Cell and Molecular Biology and of Medicine Huddinge, Karolinska Institutet, 171 77 Stockholm, Sweden; Harvard Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Bailly
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland. Electronic address: roberto.iacone@roche.com.
authors.forename: Roberto
authors.initials: R
authors.lastname: Iacone
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D058065:Diabetic Cardiomyopathies / Q000473:pathology*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006984:Hypertrophy; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D010641:Phenotype; D012518:Sarcomeres / Q000187:drug effects / Q000473:pathology; D054852:Small Molecule Libraries / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D054852:Small Molecule Libraries