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.

Human Induced Pluripotent Stem Cells as a Platform for Personalized and Precision Cardiovascular Medicine

“…Induced type II diabetic cardiomyopathy was also modeled in hiPSC-CMs following prolonged exposure to "diabetic milieu" consisting of a combination of glucose, ET-1, and cortisol (61). Gene set enrichment analysis (GSEA) using RNA-sequencing gene expression data showed significant upregulation in metabolic genes involved in the tricarboxylic acid (TCA) cycle (e.g., PDK1), mitochondrial electron transport chain (e.g., CYCS), glucose metabolism (e.g., ENO2), cell adhesion (e.g., integrins), and extracellular matrix deposition (e.g., collagens), whereas downregulation was observed in genes related to protein synthesis and the cellular response to dysfunctional protein production (e.g., ATF4 and CHOP10).…”

Inherited heart disease – what can we expect from the second decade of human iPS cell research?

“…The ambition to implement hiPSC‐CMs in precision medicine partially relies on their ability to predict patients’ response to administered drugs. Recent studies provide optimism in this direction 15, 63, 74, although additional consent and focussed investigations will be needed to determine the extent to which individual variability can be distinguished in the hiPSC‐CMs, including mild or severe, acute, early or late responses. Of note, all studies so far have been based on a small number of patients per group and were conducted retrospectively.…”

Is Transforming Stem Cells to Pancreatic Beta Cells Still the Holy Grail for Type 2 Diabetes?

“…iPS cells can also serve as a valuable resource in the absence of cellular or animal models mimicking human diseases. Various disease-specific human iPS cells have been generated including type 1 and type 2 diabetes, complex diseases such as diabetic cardiomyopathy, and several monogenic diseases which enabled investigators to explore human diseases in petri dishes [42–44]. A recent study from our group showed feasibility of using human iPS cells in modeling diabetic complications.…”