scholarly journals Induced pluripotent stem cell-derived cardiomyocytes for cardiovascular disease modeling and drug screening

2013 ◽  
Vol 4 (6) ◽  
pp. 150 ◽  
Author(s):  
Arun Sharma ◽  
Joseph C Wu ◽  
Sean M Wu
Keyword(s):  
Cardiovascular Disease ◽  
Stem Cell ◽  
Drug Screening ◽  
Pluripotent Stem Cell ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent

scholarly journals Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Afford New Opportunities in Inherited Cardiovascular Disease Modeling

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Daniel R. Bayzigitov ◽  
Sergey P. Medvedev ◽  
Elena V. Dementyeva ◽  
Sevda A. Bayramova ◽  
Evgeny A. Pokushalov ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Molecular Mechanisms ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Model Systems ◽  
Laboratory Animals ◽  
Patient Specific ◽  
Induced Pluripotent

Fundamental studies of molecular and cellular mechanisms of cardiovascular disease pathogenesis are required to create more effective and safer methods of their therapy. The studies can be carried out only when model systems that fully recapitulate pathological phenotype seen in patients are used. Application of laboratory animals for cardiovascular disease modeling is limited because of physiological differences with humans. Since discovery of induced pluripotency generating induced pluripotent stem cells has become a breakthrough technology in human disease modeling. In this review, we discuss a progress that has been made in modeling inherited arrhythmias and cardiomyopathies, studying molecular mechanisms of the diseases, and searching for and testing drug compounds using patient-specific induced pluripotent stem cell-derived cardiomyocytes.

scholarly journals Drug Development and the Use of Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Disease Modeling and Drug Toxicity Screening

2020 ◽  
Vol 21 (19) ◽  
pp. 7320
Author(s):  
Paz Ovics ◽  
Danielle Regev ◽  
Polina Baskin ◽  
Mor Davidor ◽  
Yuval Shemer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Drug Development ◽  
Drug Screening ◽  
Pluripotent Stem Cell ◽  
Disease Modeling ◽  
Heart Diseases ◽  
Induced Pluripotent Stem Cell ◽  
Drug Reactions ◽  
Novel Drugs ◽  
Induced Pluripotent

Over the years, numerous groups have employed human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) as a superb human-compatible model for investigating the function and dysfunction of cardiomyocytes, drug screening and toxicity, disease modeling and for the development of novel drugs for heart diseases. In this review, we discuss the broad use of iPSC-CMs for drug development and disease modeling, in two related themes. In the first theme—drug development, adverse drug reactions, mechanisms of cardiotoxicity and the need for efficient drug screening protocols—we discuss the critical need to screen old and new drugs, the process of drug development, marketing and Adverse Drug reactions (ADRs), drug-induced cardiotoxicity, safety screening during drug development, drug development and patient-specific effect and different mechanisms of ADRs. In the second theme—using iPSC-CMs for disease modeling and developing novel drugs for heart diseases—we discuss the rationale for using iPSC-CMs and modeling acquired and inherited heart diseases with iPSC-CMs.

scholarly journals NRF2 is required for structural and metabolic maturation of human induced pluripotent stem cell-derived ardiomyocytes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xinyuan Zhang ◽  
Liang Ye ◽  
Hao Xu ◽  
Qin Zhou ◽  
Bin Tan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Oxidative Phosphorylation ◽  
Pluripotent Stem Cell ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Metabolic Energy ◽  
Cell Maturation ◽  
Great Promise ◽  
Functional Changes ◽  
Induced Pluripotent

Abstract Background Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great promise for regenerative medicine and in drugs screening. Despite displaying key cardiomyocyte phenotypic characteristics, they more closely resemble fetal/neonatal cardiomyocytes and are still immature; these cells mainly rely on glucose as a substrate for metabolic energy, while mature cardiomyocytes mainly employ oxidative phosphorylation of fatty acids. Studies showed that the alteration of metabolism pattern from glycolysis to oxidative phosphorylation improve the maturity of hiPSC-CMs. As a transcription factor, accumulating evidences showed the important role of NRF2 in the regulation of energy metabolism, which directly regulates the expression of mitochondrial respiratory complexes. Therefore, we hypothesized that NRF2 is involved in the maturation of hiPSC-CMs. Methods The morphological and functional changes related to mitochondria and cell maturation were analyzed by knock-down and activation of NRF2. Results The results showed that the inhibition of NRF2 led to the retardation of cell maturation. The activation of NRF2 leads to a more mature hiPSC-CMs phenotype, as indicated by the increase of cardiac maturation markers, sarcomere length, calcium transient dynamics, the number and fusion events of mitochondria, and mitochondrial respiration. Bioinformatics analysis showed that in addition to metabolism-related genes, NRF2 also activates the expression of myocardial ion channels. Conclusions These findings indicated that NRF2 plays an important role in the maturation of hiPSC-CMs. The present work provides greater insights into the molecular regulation of hiPSC-CMs metabolism and theoretical basis in drug screening, disease modeling, and alternative treatment.

scholarly journals Disease Modeling and Disease Gene Discovery in Cardiomyopathies: A Molecular Study of Induced Pluripotent Stem Cell Generated Cardiomyocytes

2021 ◽  
Vol 22 (7) ◽  
pp. 3311
Author(s):  
Satish Kumar ◽  
Joanne E. Curran ◽  
Kashish Kumar ◽  
Erica DeLeon ◽  
Ana C. Leandro ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Disease Gene ◽  
Disease Modeling ◽  
Gene Discovery ◽  
Induced Pluripotent Stem Cell ◽  
P Value ◽  
Disease Gene Discovery ◽  
Induced Pluripotent

The in vitro modeling of cardiac development and cardiomyopathies in human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) provides opportunities to aid the discovery of genetic, molecular, and developmental changes that are causal to, or influence, cardiomyopathies and related diseases. To better understand the functional and disease modeling potential of iPSC-differentiated CMs and to provide a proof of principle for large, epidemiological-scale disease gene discovery approaches into cardiomyopathies, well-characterized CMs, generated from validated iPSCs of 12 individuals who belong to four sibships, and one of whom reported a major adverse cardiac event (MACE), were analyzed by genome-wide mRNA sequencing. The generated CMs expressed CM-specific genes and were highly concordant in their total expressed transcriptome across the 12 samples (correlation coefficient at 95% CI =0.92 ± 0.02). The functional annotation and enrichment analysis of the 2116 genes that were significantly upregulated in CMs suggest that generated CMs have a transcriptomic and functional profile of immature atrial-like CMs; however, the CMs-upregulated transcriptome also showed high overlap and significant enrichment in primary cardiomyocyte (p-value = 4.36 × 10−9), primary heart tissue (p-value = 1.37 × 10−41) and cardiomyopathy (p-value = 1.13 × 10−21) associated gene sets. Modeling the effect of MACE in the generated CMs-upregulated transcriptome identified gene expression phenotypes consistent with the predisposition of the MACE-affected sibship to arrhythmia, prothrombotic, and atherosclerosis risk.

scholarly journals Machine Learning Approach to Automated Quality Identification of Human Induced Pluripotent Stem Cell Colony Images

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Henry Joutsijoki ◽  
Markus Haponen ◽  
Jyrki Rasku ◽  
Katriina Aalto-Setälä ◽  
Martti Juhola
Keyword(s):  
Machine Learning ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Patient Specific ◽  
Support Vector ◽  
Ips Cell ◽  
Cell Technology ◽  
Induced Pluripotent

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.

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

2020 ◽  
Vol 21 (19) ◽  
pp. 6997 ◽  
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.

scholarly journals Induced pluripotent stem cell-based disease modeling identifies ligand-induced decay of megalin as a cause of Donnai-Barrow syndrome

2020 ◽  
Vol 98 (1) ◽  
pp. 159-167 ◽  
Author(s):  
Julia Flemming ◽  
Maike Marczenke ◽  
Ina-Maria Rudolph ◽  
Rikke Nielsen ◽  
Tina Storm ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent

scholarly journals Investigation of de novo mutations in a schizophrenia case-parent trio by induced pluripotent stem cell-based in vitro disease modeling: convergence of schizophrenia- and autism-related cellular phenotypes

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Edit Hathy ◽  
Eszter Szabó ◽  
Nóra Varga ◽  
Zsuzsa Erdei ◽  
Csongor Tordai ◽  
...  
Keyword(s):  
Stem Cell ◽  
Dentate Gyrus ◽  
Pluripotent Stem Cell ◽  
Disease Modeling ◽  
De Novo ◽  
Disease Onset ◽  
Induced Pluripotent Stem Cell ◽  
Synaptic Function ◽  
De Novo Mutations ◽  
Induced Pluripotent

Abstract Background De novo mutations (DNMs) have been implicated in the etiology of schizophrenia (SZ), a chronic debilitating psychiatric disorder characterized by hallucinations, delusions, cognitive dysfunction, and decreased community functioning. Several DNMs have been identified by examining SZ cases and their unaffected parents; however, in most cases, the biological significance of these mutations remains elusive. To overcome this limitation, we have developed an approach of using induced pluripotent stem cell (iPSC) lines from each member of a SZ case-parent trio, in order to investigate the effects of DNMs in cellular progenies of interest, particularly in dentate gyrus neuronal progenitors. Methods We identified a male SZ patient characterized by early disease onset and negative symptoms, who is a carrier of 3 non-synonymous DNMs in genes LRRC7, KHSRP, and KIR2DL1. iPSC lines were generated from his and his parents’ peripheral blood mononuclear cells using Sendai virus-based reprogramming and differentiated into neuronal progenitor cells (NPCs) and hippocampal dentate gyrus granule cells. We used RNASeq to explore transcriptomic differences and calcium (Ca2+) imaging, cell proliferation, migration, oxidative stress, and mitochondrial assays to characterize the investigated NPC lines. Results NPCs derived from the SZ patient exhibited transcriptomic differences related to Wnt signaling, neuronal differentiation, axonal guidance and synaptic function, and decreased Ca2+ reactivity to glutamate. Moreover, we could observe increased cellular proliferation and alterations in mitochondrial quantity and morphology. Conclusions The approach of reprograming case-parent trios represents an opportunity for investigating the molecular effects of disease-causing mutations and comparing these in cell lines with reduced variation in genetic background. Our results are indicative of a partial overlap between schizophrenia and autism-related phenotypes in the investigated family. Limitations Our study investigated only one family; therefore, the generalizability of findings is limited. We could not derive iPSCs from two other siblings to test for possible genetic effects in the family that are not driven by DNMs. The transcriptomic and functional assays were limited to the NPC stage, although these variables should also be investigated at the mature neuronal stage.

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