scholarly journals Human Pluripotent Stem Cells for Modeling of Anticancer Therapy-Induced Cardiotoxicity and Cardioprotective Drug Discovery

2021 ◽  
Vol 12 ◽  
Author(s):  
Wendy Keung ◽  
Yiu-Fai Cheung
Keyword(s):  
Risk Factors ◽  
Drug Discovery ◽  
Induced Pluripotent Stem Cell ◽  
Underlying Mechanism ◽  
Anticancer Therapy ◽  
Treatment Regimens ◽  
Increased Risk ◽  
Induced Pluripotent ◽  
Novel Drug ◽  
Cardioprotective Drug

Anticancer chemotherapies have been shown to produce severe side effects, with cardiotoxicity from anthracycline being the most notable. Identifying risk factors for anticancer therapy-induced cardiotoxicity in cancer patients as well as understanding its underlying mechanism is essential to improving clinical outcomes of chemotherapy treatment regimens. Moreover, cardioprotective agents against anticancer therapy-induced cardiotoxicity are scarce. Human induced pluripotent stem cell technology offers an attractive platform for validation of potential single nucleotide polymorphism with increased risk for cardiotoxicity. Successful validation of risk factors and mechanism of cardiotoxicity would aid the development of such platform for novel drug discovery and facilitate the practice of personalized medicine.

scholarly journals hiPSC-Derived Cardiac Tissue for Disease Modeling and Drug Discovery

2020 ◽  
Vol 21 (23) ◽  
pp. 8893
Author(s):  
Junjun Li ◽  
Ying Hua ◽  
Shigeru Miyagawa ◽  
Jingbo Zhang ◽  
Lingjun Li ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Cardiac Tissue ◽  
Disease Modeling ◽  
Disease Model ◽  
Induced Pluripotent Stem Cell ◽  
Model Systems ◽  
Toxicity Screening ◽  
The Difference ◽  
Induced Pluripotent ◽  
Novel Drug

Relevant, predictive normal, or disease model systems are of vital importance for drug development. The difference between nonhuman models and humans could contribute to clinical trial failures despite ideal nonhuman results. As a potential substitute for animal models, human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) provide a powerful tool for drug toxicity screening, modeling cardiovascular diseases, and drug discovery. Here, we review recent hiPSC-CM disease models and discuss the features of hiPSC-CMs, including subtype and maturation and the tissue engineering technologies for drug assessment. Updates from the international multisite collaborators/administrations for development of novel drug discovery paradigms are also summarized.

scholarly journals Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases

2021 ◽  
Vol 22 (15) ◽  
pp. 8196
Author(s):  
Dorit Trudler ◽  
Swagata Ghatak ◽  
Stuart A. Lipton
Keyword(s):  
Drug Discovery ◽  
Animal Models ◽  
Neurodegenerative Diseases ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Neural Function ◽  
Neural Cells ◽  
Human Samples ◽  
Healthy Donors ◽  
Induced Pluripotent

Neurodegenerative diseases affect millions of people worldwide and are characterized by the chronic and progressive deterioration of neural function. Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), represent a huge social and economic burden due to increasing prevalence in our aging society, severity of symptoms, and lack of effective disease-modifying therapies. This lack of effective treatments is partly due to a lack of reliable models. Modeling neurodegenerative diseases is difficult because of poor access to human samples (restricted in general to postmortem tissue) and limited knowledge of disease mechanisms in a human context. Animal models play an instrumental role in understanding these diseases but fail to comprehensively represent the full extent of disease due to critical differences between humans and other mammals. The advent of human-induced pluripotent stem cell (hiPSC) technology presents an advantageous system that complements animal models of neurodegenerative diseases. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors now allow disease modeling using human samples that can be used for drug discovery.

scholarly journals Hereditary Optic Neuropathies: Induced Pluripotent Stem Cell-Based 2D/3D Approaches

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 112
Author(s):  
Marta García-López ◽  
Joaquín Arenas ◽  
M. Esther Gallardo
Keyword(s):  
Stem Cell ◽  
Retinal Ganglion Cells ◽  
Pluripotent Stem Cell ◽  
Ganglion Cells ◽  
Genetic Disorders ◽  
Three Dimensional ◽  
Induced Pluripotent Stem Cell ◽  
Underlying Mechanism ◽  
Retinal Ganglion ◽  
Induced Pluripotent

Inherited optic neuropathies share visual impairment due to the degeneration of retinal ganglion cells (RGCs) as the hallmark of the disease. This group of genetic disorders are caused by mutations in nuclear genes or in the mitochondrial DNA (mtDNA). An impaired mitochondrial function is the underlying mechanism of these diseases. Currently, optic neuropathies lack an effective treatment, and the implementation of induced pluripotent stem cell (iPSC) technology would entail a huge step forward. The generation of iPSC-derived RGCs would allow faithfully modeling these disorders, and these RGCs would represent an appealing platform for drug screening as well, paving the way for a proper therapy. Here, we review the ongoing two-dimensional (2D) and three-dimensional (3D) approaches based on iPSCs and their applications, taking into account the more innovative technologies, which include tissue engineering or microfluidics.

scholarly journals Personalized medicine in cardio-oncology: the role of induced pluripotent stem cell

2019 ◽  
Vol 115 (5) ◽  
pp. 949-959 ◽  
Author(s):  
Nazish Sayed ◽  
Mohamed Ameen ◽  
Joseph C Wu
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Association Studies ◽  
Induced Pluripotent Stem Cell ◽  
Human Diseases ◽  
Genome Wide Association Studies ◽  
Genomic Variants ◽  
Induced Pluripotent

Abstract Treatment of cancer has evolved in the last decade with the introduction of new therapies. Despite these successes, the lingering cardiotoxic side-effects from chemotherapy remain a major cause of morbidity and mortality in cancer survivors. These effects can develop acutely during treatment, or even years later. Although many risk factors can be identified prior to beginning therapy, unexpected toxicity still occurs, often with lasting consequences. Specifically, cardiotoxicity results in cardiac cell death, eventually leading to cardiomyopathy and heart failure. Certain risk factors may predispose an individual to experiencing adverse cardiovascular effects, and when unexpected cardiotoxicity occurs, it is generally managed with supportive care. Animal models of chemotherapy-induced cardiotoxicity have provided some mechanistic insights, but the precise mechanisms by which these drugs affect the heart remains unknown. Moreover, the genetic rationale as to why some patients are more susceptible to developing cardiotoxicity has yet to be determined. Many genome-wide association studies have identified genomic variants that could be associated with chemotherapy-induced cardiotoxicity, but the lack of validation has made these studies more speculative rather than definitive. With the advent of human induced pluripotent stem cell (iPSC) technology, researchers not only have the opportunity to model human diseases, but also to screen drugs for their efficacy and toxicity using human cell models. Furthermore, it allows us to conduct validation studies to confirm the role of genomic variants in human diseases. In this review, we discuss the role of iPSCs in modelling chemotherapy-induced cardiotoxicity.

Drug discovery using induced pluripotent stem cell models of neurodegenerative and ocular diseases

2017 ◽  
Vol 177 ◽  
pp. 32-43 ◽  
Author(s):  
Sandy S.C. Hung ◽  
Shahnaz Khan ◽  
Camden Y. Lo ◽  
Alex W. Hewitt ◽  
Raymond C.B. Wong
Keyword(s):  
Stem Cell ◽  
Drug Discovery ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Ocular Diseases ◽  
Cell Models ◽  
Induced Pluripotent ◽  
Stem Cell Models

scholarly journals A Novel High-Content Screening-Based Method for Anti-Trypanosoma cruzi Drug Discovery Using Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Diogo Crispim Nascimento Portella ◽  
Erik Aranha Rossi ◽  
Bruno Diaz Paredes ◽  
Tanira Matutino Bastos ◽  
Cássio Santana Meira ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Imaging System ◽  
Rapid Assessment ◽  
Chronic Phase ◽  
Induced Pluripotent Stem Cell ◽  
High Content Screening ◽  
Reference Drug ◽  
Induced Pluripotent

Chagas disease is caused by Trypanosoma cruzi infection and remains a relevant cause of chronic heart failure in Latin America. The pharmacological arsenal for Chagas disease is limited, and the available anti-T. cruzi drugs are not effective when administered during the chronic phase. Cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) have the potential to accelerate the process of drug discovery for Chagas disease, through predictive preclinical assays in target human cells. Here, we aimed to establish a novel high-content screening- (HCS-) based method using hiPSC-CMs to simultaneously evaluate anti-T. cruzi activity and cardiotoxicity of chemical compounds. To provide proof-of-concept data, the reference drug benznidazole and three compounds with known anti-T. cruzi activity (a betulinic acid derivative named BA5 and two thiazolidinone compounds named GT5A and GT5B) were evaluated in the assay. hiPSC-CMs were infected with T. cruzi and incubated for 48 h with serial dilutions of the compounds for determination of EC50 and CC50 values. Automated multiparametric analyses were performed using an automated high-content imaging system. Sublethal toxicity measurements were evaluated through morphological measurements related to the integrity of the cytoskeleton by phalloidin staining, nuclear score by Hoechst 33342 staining, mitochondria score following MitoTracker staining, and quantification of NT-pro-BNP, a peptide released upon mechanical myocardial stress. The compounds showed EC50 values for anti-T. cruzi activity similar to those previously described for other cell types, and GT5B showed a pronounced trypanocidal activity in hiPSC-CMs. Sublethal changes in cytoskeletal and nucleus scores correlated with NT-pro-BNP levels in the culture supernatant. Mitochondrial score changes were associated with increased cytotoxicity. The assay was feasible and allowed rapid assessment of anti-T. cruzi action of the compounds, in addition to cardiotoxicity parameters. The utilization of hiPSC-CMs in the drug development workflow for Chagas disease may help in the identification of novel compounds.

scholarly journals Microglial signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate inability to activate inflammasome

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Katharina Cosker ◽  
Anna Mallach ◽  
Janhavi Limaye ◽  
Thomas M. Piers ◽  
James Staddon ◽  
...  
Keyword(s):  
Pluripotent Stem Cell ◽  
Late Onset ◽  
Apoptotic Cell ◽  
Cell Damage ◽  
Induced Pluripotent Stem Cell ◽  
Endogenous Ligand ◽  
Increased Risk ◽  
Soluble Trem2 ◽  
Signalling Cascades ◽  
Induced Pluripotent

AbstractThe R47H variant of the microglial membrane receptor TREM2 is linked to increased risk of late onset Alzheimer’s disease. Human induced pluripotent stem cell derived microglia (iPS-Mg) from patient iPSC lines expressing the AD-linked R47Hhet TREM2 variant, common variant (Cv) or an R47Hhom CRISPR edited line and its isogeneic control, demonstrated that R47H-expressing iPS-Mg expressed a deficit in signal transduction in response to the TREM2 endogenous ligand phosphatidylserine with reduced pSYK-pERK1/2 signalling and a reduced NLRP3 inflammasome response, (including ASC speck formation, Caspase-1 activation and IL-1beta secretion). Apoptotic cell phagocytosis and soluble TREM2 shedding were unaltered, suggesting a disjoint between these pathways and the signalling cascades downstream of TREM2 in R47H-expressing iPS-Mg, whilst metabolic deficits in glycolytic capacity and maximum respiration were reversed when R47H expressing iPS-Mg were exposed to PS+ expressing cells. These findings suggest that R47H-expressing microglia are unable to respond fully to cell damage signals such as phosphatidylserine, which may contribute to the progression of neurodegeneration in late-onset AD.

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