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Cell Rep. 2014 Nov 6;9(3):810-21. doi: 10.1016/j.celrep.2014.09.055. Epub 2014 Oct 30.

Disease modeling and phenotypic drug screening for diabetic cardiomyopathy using human induced pluripotent stem cells.

Author information

1
Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
2
Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
3
Center for Cell Imaging and Nano Analytics, Biozentrum, Department for Biosystems Science and Engineering, University of Basel, 4058 Basel, Switzerland.
4
The Cardiovascular Research Center, Richard B. Simches Research Center, Massachusetts General Hospital, Suite 3201, Boston, MA 02114, USA.
5
Cellular Dynamics International, Madison, WI 53711, USA.
6
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.
7
Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland. Electronic address: roberto.iacone@roche.com.

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.

PMID:
25437537
DOI:
10.1016/j.celrep.2014.09.055
[Indexed for MEDLINE]
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