Severe DCM phenotype of patient harboring RBM20 mutation S635A can be modeled by patient-specific induced pluripotent stem cell-derived cardiomyocytes

The focus of this research is on automated identification of the quality of human induced pluripotent stem cell (iPSC) colony images. iPS cell technology is a contemporary method by which the patient’s cells are reprogrammed back to stem cells and are differentiated to any cell type wanted. iPS cell technology will be used in future to patient specific drug screening, disease modeling, and tissue repairing, for instance. However, there are technical challenges before iPS cell technology can be used in practice and one of them is quality control of growing iPSC colonies which is currently done manually but is unfeasible solution in large-scale cultures. The monitoring problem returns to image analysis and classification problem. In this paper, we tackle this problem using machine learning methods such as multiclass Support Vector Machines and several baseline methods together with Scaled Invariant Feature Transformation based features. We perform over 80 test arrangements and do a thorough parameter value search. The best accuracy (62.4%) for classification was obtained by using ak-NN classifier showing improved accuracy compared to earlier studies.

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Abstract 142: Modeling Drug-Induced Long QT Syndrome with Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Circulation Research ◽

10.1161/res.113.suppl_1.a142 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Francesca Stillitano ◽

Ioannis Karakikes ◽

Chi-wai Kong ◽

Brett Martinelli ◽

Ronald Li ◽

...

Keyword(s):

Stem Cell ◽

Pluripotent Stem Cell ◽

Induced Pluripotent Stem Cell ◽

Patient Specific ◽

Dependent Manner ◽

Long Qt ◽

Drug Induced ◽

Qt Syndrome ◽

Induced Pluripotent ◽

Dose Dependent

Long QT syndrome (LQTS) is characterized by prolonged cardiac repolarization time and increased risk of ventricular arrhythmia. LQTS can be either inherited or induced notably after drugs intake. Mutations in genes encoding cardiac ion channels have been reported to underlie inherited LQTS. In contrast, drug-induced LQTS (diLQTS) most frequently arises from altered function of the hERG channel; the risk of developing diLQTS varies largely between subjects and most people who have life-threatening diLQTS have no known genetic risk factors. We investigated whether the susceptibility to develop diLQTS observed in vivo can be recapitulated in vitro using patient-specific induced pluripotent stem cell (iPSC) technology. We collected skin fibroblasts from ten subjects who developed significant diLQTS after administration of Sotalol and/or Erythromycin. Ten other individuals who displayed no changes in QT interval after administration of the same drugs, were selected. iPSC were generated by retroviral delivery of Oct4, Sox2, Nanog and Klf4 in 17 of the 20 individuals. We report preliminary results obtained from iPSC-derived cardiomyocytes (iPSC-CMs) of two subjects. All experiments were performed in a blinded fashion without knowledge of the associated clinical phenotype. Cardiac differentiation of iPSC resulted in the generation of spontaneously beating embryoid bodies. iPSC-CMs showed positive staining for TNNT2, ACTN2 and Cx43. Gene expression analysis confirmed the expression of NKX2.5, MLC2v, MYH6 and MYH7, and of the relevant KCNH2 gene. The two lines had similar basal electrophysiological properties as assessed by measurements of action potential (AP) by patch-clamp technique and extracellular field potentials (FP) using micro-electrode array (MEA). E4031, a classical HERG blocker, significantly prolonged the FP duration (FPD) in a dose-dependent manner in both lines (EC50: 30.19 and 51.57 respectively). When both Sotalol and Erythromicin were used, FPD was prolonged in one of the two samples in a dose-dependent manner (EC50Sotalol: 100; EC50Erythr: 9.64) while drug response was blunted in the other cell line. This study suggests that patient-specific iPSC can be used to model the functional abnormalities observed in acquired diLQTS.

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Patient-Specific and Gene-Corrected Induced Pluripotent Stem Cell-Derived Cardiomyocytes Elucidate Single-Cell Phenotype of Short QT Syndrome

Circulation Research ◽

10.1161/circresaha.118.313518 ◽

2019 ◽

Vol 124 (1) ◽

pp. 66-78 ◽

Cited By ~ 10

Author(s):

Fengfeng Guo ◽

Yaxun Sun ◽

Xiaochen Wang ◽

Hao Wang ◽

Jue Wang ◽

...

Keyword(s):

Stem Cell ◽

Single Cell ◽

Pluripotent Stem Cell ◽

Induced Pluripotent Stem Cell ◽

Patient Specific ◽

Cell Phenotype ◽

Short Qt Syndrome ◽

Qt Syndrome ◽

Induced Pluripotent

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Spontaneous Generation of Patient-Specific Retinal Pigment Epithelial Cells Using Induced Pluripotent Stem Cell Technology

Working with Stem Cells ◽

10.1007/978-3-319-30582-0_9 ◽

2016 ◽

pp. 143-161

Author(s):

David A. Carter ◽

Britta Nommiste ◽

Pete J. Coffey ◽

Amanda-Jayne F. Carr

Keyword(s):

Stem Cell ◽

Pluripotent Stem Cell ◽

Retinal Pigment ◽

Induced Pluripotent Stem Cell ◽

Retinal Pigment Epithelial Cells ◽

Patient Specific ◽

Spontaneous Generation ◽

Pigment Epithelial ◽

Induced Pluripotent ◽

Pigment Epithelial Cells

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“Betwixt Mine Eye and Heart a League Is Took”: The Progress of Induced Pluripotent Stem-Cell-Based Models of Dystrophin-Associated Cardiomyopathy

International Journal of Molecular Sciences ◽

10.3390/ijms21196997 ◽

2020 ◽

Vol 21 (19) ◽

pp. 6997 ◽

Cited By ~ 1

Author(s):

Davide Rovina ◽

Elisa Castiglioni ◽

Francesco Niro ◽

Sara Mallia ◽

Giulio Pompilio ◽

...

Keyword(s):

Stem Cell ◽

Muscular Dystrophy ◽

Pluripotent Stem Cell ◽

Disease Modeling ◽

Disease Model ◽

Induced Pluripotent Stem Cell ◽

Patient Specific ◽

Great Promise ◽

Cord Injury ◽

Induced Pluripotent

The ultimate goal of precision disease modeling is to artificially recreate the disease of affected people in a highly controllable and adaptable external environment. This field has rapidly advanced which is evident from the application of patient-specific pluripotent stem-cell-derived precision therapies in numerous clinical trials aimed at a diverse set of diseases such as macular degeneration, heart disease, spinal cord injury, graft-versus-host disease, and muscular dystrophy. Despite the existence of semi-adequate treatments for tempering skeletal muscle degeneration in dystrophic patients, nonischemic cardiomyopathy remains one of the primary causes of death. Therefore, cardiovascular cells derived from muscular dystrophy patients’ induced pluripotent stem cells are well suited to mimic dystrophin-associated cardiomyopathy and hold great promise for the development of future fully effective therapies. The purpose of this article is to convey the realities of employing precision disease models of dystrophin-associated cardiomyopathy. This is achieved by discussing, as suggested in the title echoing William Shakespeare’s words, the settlements (or “leagues”) made by researchers to manage the constraints (“betwixt mine eye and heart”) distancing them from achieving a perfect precision disease model.

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