scholarly journals Drug Discovery Models and Toxicity Testing Using Embryonic and Induced Pluripotent Stem-Cell-Derived Cardiac and Neuronal Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Rahul S. Deshmukh ◽  
Krisztián A Kovács ◽  
András Dinnyés
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Drug Development ◽  
Disease Modeling ◽  
Embryonic Stem ◽  
Toxicity Testing ◽  
Induced Pluripotent Stem Cell ◽  
Research Application ◽  
Practical Development ◽  
Induced Pluripotent

Development of induced pluripotent stem cells (iPSCs) using forced expression of specific sets of transcription factors has changed the field of stem cell research extensively. Two important limitations for research application of embryonic stem cells (ESCs), namely, ethical and immunological issues, can be circumvented using iPSCs. Since the development of first iPSCs, tremendous effort has been directed to the development of methods to increase the efficiency of the process and to reduce the extent of genomic modifications associated with the reprogramming procedure. The established lineage-specific differentiation protocols developed for ESCs are being applied to iPSCs, as they have great potential in regenerative medicine for cell therapy, disease modeling either for drug development or for fundamental science, and, last but not least, toxicity testing. This paper reviews efforts aimed at practical development of iPSC differentiation to neural/cardiac lineages and further the use of these iPSCs-derived cells for drug development and toxicity testing.

scholarly journals A Novel Purification Method of Murine Embryonic Stem Cell– and Human-Induced Pluripotent Stem Cell–Derived Cardiomyocytes by Simple Manual Dissociation

2012 ◽  
Vol 17 (5) ◽  
pp. 683-691 ◽  
Author(s):  
Tadahiro Shinozawa ◽  
Hatsue Furukawa ◽  
Eimei Sato ◽  
Kenji Takami
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Pluripotent Stem Cell ◽  
Embryonic Stem ◽  
Induced Pluripotent Stem Cell ◽  
Drug Induced ◽  
Thin Glass ◽  
Murine Embryonic Stem Cell ◽  
Induced Pluripotent

Cardiomyocytes derived from embryonic stem cells (ES-CMs) and induced pluripotent stem cells (iPS-CMs) are useful for toxicity and pharmacology screening. In the present study, we found that cardiomyocyte-rich beating cell clusters (CCs) emerged from murine embryonic stem cell (mESC)–derived beating EBs and from human-induced pluripotent stem cell (hiPSC)–derived beating EBs dissociated by gentle pipetting with a thin glass pipette. The percentage of cardiac troponin T (cTnT)–positive cells in the beating CCs obtained from mESC-derived and hiPSC-derived beating EBs was higher (81.5% and 91.6%, respectively) than in beating-undissociated EBs (13.7% and 67.1%, respectively). For mESCs, the yield of cTnT-positive cells from beating CCs was estimated to be 1.6 times higher than that of beating EBs. The bromodeoxyuridine labeling index of mouse ES-CMs and human iPS-CMs in beating CCs was 1.5- and 3.2-fold, respectively, greater than those in beating EBs. To investigate the utility of the cells in toxicity assessment, we showed that doxorubicin, a cardiotoxic drug, induced myofilament disruption in cardiomyocytes isolated by this method. This simple method enables preparation of mouse ES-CMs and human iPS-CMs with better proliferative activity than beating EBs not dissociated by pipetting, and the cardiomyocytes are useful for drug-induced myocardial toxicity testing.

scholarly journals Myofibrillar Structural Variability Underlies Contractile Function in Stem Cell-Derived Cardiomyocytes

2020 ◽  
Author(s):  
Kathryn Ufford ◽  
Sabrina Friedline ◽  
Zhaowen Tong ◽  
Vi T. Tang ◽  
Amani S. Dobbs ◽  
...  
Keyword(s):  
Stem Cell ◽  
Disease Modeling ◽  
Contractile Function ◽  
Embryonic Stem ◽  
Induced Pluripotent Stem Cell ◽  
Primary Objective ◽  
Intrinsic Variability ◽  
Elastic Substrates ◽  
Induced Pluripotent ◽  
The Impact

SummaryDisease modeling and pharmaceutical testing using cardiomyocytes derived from induced pluripotent stem cell (iPSC-CMs) requires accurate assessment of contractile function. Micropatterning iPSC-CMs on elastic substrates controls cell shape and alignment to enable contractile studies, but the determinants of intrinsic variability in this system have been incompletely characterized. The primary objective of this study was to determine the impact of myofibrillar structure on contractile function in iPSC-CMs. After labeling micropatterned iPSC-CMs with a cell permeant F-actin dye, we imaged both myofibrillar structure and contractile function. Using automated myofibrillar image analysis, we demonstrate that myofibrillar abundance is widely variable among individual iPSC-CMs and strongly correlates with contractile function. This variability is not reduced by subcloning from single iPSCs to reduce genetic heterogeneity, persists with two different iPSC-CM purification methods, and similarly is present for embryonic stem cell-derived cardiomyocytes. This analysis provides compelling evidence that myofibrillar structure should be quantified and controlled for in studies investigating contractile function in iPSC-CMs.

scholarly journals The mitochondrial protein CHCHD2 primes the differentiation potential of human induced pluripotent stem cells to neuroectodermal lineages

2016 ◽  
Vol 215 (2) ◽  
pp. 187-202 ◽  
Author(s):  
Lili Zhu ◽  
Aurora Gomez-Duran ◽  
Gabriele Saretzki ◽  
Shibo Jin ◽  
Katarzyna Tilgner ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Pluripotent Stem Cells ◽  
Large Scale ◽  
Mitochondrial Protein ◽  
Embryonic Stem ◽  
Induced Pluripotent Stem Cell ◽  
Clonal Variation ◽  
Differentiation Potential ◽  
Induced Pluripotent

Human induced pluripotent stem cell (hiPSC) utility is limited by variations in the ability of these cells to undergo lineage-specific differentiation. We have undertaken a transcriptional comparison of human embryonic stem cell (hESC) lines and hiPSC lines and have shown that hiPSCs are inferior in their ability to undergo neuroectodermal differentiation. Among the differentially expressed candidates between hESCs and hiPSCs, we identified a mitochondrial protein, CHCHD2, whose expression seems to correlate with neuroectodermal differentiation potential of pluripotent stem cells. We provide evidence that hiPSC variability with respect to CHCHD2 expression and differentiation potential is caused by clonal variation during the reprogramming process and that CHCHD2 primes neuroectodermal differentiation of hESCs and hiPSCs by binding and sequestering SMAD4 to the mitochondria, resulting in suppression of the activity of the TGFβ signaling pathway. Using CHCHD2 as a marker for assessing and comparing the hiPSC clonal and/or line differentiation potential provides a tool for large scale differentiation and hiPSC banking studies.

A PRC2-Dependent Repressive Role of PRDM14 in Human Embryonic Stem Cells and Induced Pluripotent Stem Cell Reprogramming

Stem Cells ◽  
2013 ◽  
Vol 31 (4) ◽  
pp. 682-692 ◽  
Author(s):  
Yun-Shen Chan ◽  
Jonathan Göke ◽  
Xinyi Lu ◽  
Nandini Venkatesan ◽  
Bo Feng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Pluripotent Stem Cell ◽  
Embryonic Stem ◽  
Induced Pluripotent Stem Cell ◽  
Cell Reprogramming ◽  
Induced Pluripotent

Increase of sensitivity to mechanical stimulus after transplantation of murine induced pluripotent stem cell–derived astrocytes in a rat spinal cord injury model

2011 ◽  
Vol 15 (6) ◽  
pp. 582-593 ◽  
Author(s):  
Koichi Hayashi ◽  
Masayuki Hashimoto ◽  
Masao Koda ◽  
Atsuhiko T. Naito ◽  
Atsushi Murata ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Embryonic Stem ◽  
Induced Pluripotent Stem Cell ◽  
Mechanical Stimulus ◽  
Cord Injury ◽  
Induced Pluripotent

Object Clinical use of autologous induced pluripotent stem cells (iPSCs) could circumvent immune rejection and bioethical issues associated with embryonic stem cells. Spinal cord injury (SCI) is a devastating trauma with long-lasting disability, and current therapeutic approaches are not satisfactory. In the present study, the authors used the neural stem sphere (NSS) method to differentiate iPSCs into astrocytes, which were evaluated after their transplantation into injured rat spinal cords. Methods Induced pluripotent stem cell–derived astrocytes were differentiated using the NSS method and injected 3 and 7 days after spinal contusion–based SCI. Control rats were injected with DMEM in the same manner. Locomotor recovery was assessed for 8 weeks, and sensory and locomotion tests were evaluated at 8 weeks. Immunohistological parameters were then assessed. Results Transplant recipients lived for 8 weeks without tumor formation. Transplanted cells stretched their processes along the longitudinal axis, but they did not merge with the processes of host GFAP-positive astrocytes. Locomotion was assessed in 3 ways, but none of the tests detected statistically significant improvements compared with DMEM-treated control rats after 8 weeks. Rather, iPSC transplantation caused even greater sensitivity to mechanical stimulus than DMEM treatment. Conclusions Astrocytes can be generated by serum treatment of NSS-generated cells derived from iPSCs. However, transplantation of such cells is poorly suited for repairing SCI.

scholarly journals Histone Deacetylase Inhibitors in Cell Pluripotency, Differentiation, and Reprogramming

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Androniki Kretsovali ◽  
Christiana Hadjimichael ◽  
Nikolaos Charmpilas
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Ectopic Expression ◽  
Embryonic Stem ◽  
Induced Pluripotent Stem Cell ◽  
Stem Cell Differentiation ◽  
Induced Pluripotent

Histone deacetylase inhibitors (HDACi) are small molecules that have important and pleiotropic effects on cell homeostasis. Under distinct developmental conditions, they can promote either self-renewal or differentiation of embryonic stem cells. In addition, they can promote directed differentiation of embryonic and tissue-specific stem cells along the neuronal, cardiomyocytic, and hepatic lineages. They have been used to facilitate embryo development following somatic cell nuclear transfer and induced pluripotent stem cell derivation by ectopic expression of pluripotency factors. In the latter method, these molecules not only increase effectiveness, but can also render the induction independent of the oncogenes c-Myc and Klf4. Here we review the molecular pathways that are involved in the functions of HDAC inhibitors on stem cell differentiation and reprogramming of somatic cells into pluripotency. Deciphering the mechanisms of HDAC inhibitor actions is very important to enable their exploitation for efficient and simple tissue regeneration therapies.

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.

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