Human Pluripotent Stem Cells and Drug Discovery: A New Beginning

2016 ◽  
Vol 1 (1) ◽  
pp. 27
Author(s):  
Vinod Verma ◽  
A. Mehta ◽  
S.J.S. Flora
Keyword(s):  
Stem Cells ◽  
Drug Discovery ◽  
Pluripotent Stem Cells ◽  
Cost Effective ◽  
Cell Types ◽  
In Vitro Models ◽  
Human Pluripotent Stem Cells ◽  
Specific Cell ◽  
Attrition Rates

Human pluripotent stem cells (hPSCs) offer unique opportunities to discover and develop a new generation of drugs. Their ability to differentiate into virtually any cell type renders them a cost-effective, renewable source of tissue-specific cell types capable of predicting human responses towards novel chemical entities. Using these improved in vitro models based on physiologically relevant human cell types could result in identifying highly precise and safe compounds, thereby reducing drug attrition rates. Moreover, ability to develop humanised disease models for patient-stratified drug screening makes hPSCs an impeccable tool in translational medicine. In this mini-review we focus on the positives and negatives of utilising hPSC-derived cell types as drug discovery platforms with special emphasis on cardio-, hepato- and embryotoxicity.

scholarly journals Modulating cell state to enhance suspension expansion of human pluripotent stem cells

2018 ◽  
Vol 115 (25) ◽  
pp. 6369-6374 ◽  
Author(s):  
Yonatan Y. Lipsitz ◽  
Curtis Woodford ◽  
Ting Yin ◽  
Jacob H. Hanna ◽  
Peter W. Zandstra
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Large Scale ◽  
Cell Types ◽  
Human Pluripotent Stem Cells ◽  
The Body ◽  
Altered Expression ◽  
Pancreatic Progenitors ◽  
Erk Inhibition

The development of cell-based therapies to replace missing or damaged tissues within the body or generate cells with a unique biological activity requires a reliable and accessible source of cells. Human pluripotent stem cells (hPSC) have emerged as a strong candidate cell source capable of extended propagation in vitro and differentiation to clinically relevant cell types. However, the application of hPSC in cell-based therapies requires overcoming yield limitations in large-scale hPSC manufacturing. We explored methods to convert hPSC to alternative states of pluripotency with advantageous bioprocessing properties, identifying a suspension-based small-molecule and cytokine combination that supports increased single-cell survival efficiency, faster growth rates, higher densities, and greater expansion than control hPSC cultures. ERK inhibition was found to be essential for conversion to this altered state, but once converted, ERK inhibition led to a loss of pluripotent phenotype in suspension. The resulting suspension medium formulation enabled hPSC suspension yields 5.7 ± 0.2-fold greater than conventional hPSC in 6 d, for at least five passages. Treated cells remained pluripotent, karyotypically normal, and capable of differentiating into all germ layers. Treated cells could also be integrated into directed differentiated strategies as demonstrated by the generation of pancreatic progenitors (NKX6.1+/PDX1+ cells). Enhanced suspension-yield hPSC displayed higher oxidative metabolism and altered expression of adhesion-related genes. The enhanced bioprocess properties of this alternative pluripotent state provide a strategy to overcome cell manufacturing limitations of hPSC.

scholarly journals Induced pluripotent stem cells-derived neurons from patients with Friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Pauline Georges ◽  
Maria-Gabriela Boza-Moran ◽  
Jacqueline Gide ◽  
Georges Arielle Pêche ◽  
Benjamin Forêt ◽  
...  
Keyword(s):  
Stem Cells ◽  
Drug Discovery ◽  
Pluripotent Stem Cells ◽  
Friedreich Ataxia ◽  
Cell Types ◽  
Differential Sensitivity ◽  
Human Ipscs ◽  
Induced Pluripotent ◽  
Species Specific

Abstract Translation of pharmacological results from in vitro cell testing to clinical trials is challenging. One of the causes that may underlie these discrepant results is the lack of the phenotypic or species-specific relevance of the tested cells; today, this lack of relevance may be reduced by relying on cells differentiated from human pluripotent stem cells. To analyse the benefits provided by this approach, we chose to focus on Friedreich ataxia, a neurodegenerative condition for which the recent clinical testing of two compounds was not successful. These compounds, namely, resveratrol and nicotinamide, were selected because they had been shown to stimulate the expression of frataxin in fibroblasts and lymphoblastoid cells. Our results indicated that these compounds failed to do so in iPSC-derived neurons generated from two patients with Friedreich ataxia. By comparing the effects of both molecules on different cell types that may be considered to be non-relevant for the disease, such as fibroblasts, or more relevant to the disease, such as neurons differentiated from iPSCs, a differential response was observed; this response suggests the importance of developing more predictive in vitro systems for drug discovery. Our results demonstrate the value of utilizing human iPSCs early in drug discovery to improve translational predictability.

Human Pluripotent Stem Cells as In Vitro Models for Retinal Development and Disease

2018 ◽  
pp. 17-49 ◽  
Author(s):  
Akshayalakshmi Sridhar ◽  
Kirstin B. Langer ◽  
Clarisse M. Fligor ◽  
Matthew Steinhart ◽  
Casey A. Miller ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Retinal Development ◽  
In Vitro Models ◽  
Human Pluripotent Stem Cells

scholarly journals Human pluripotent stem cells for the modelling and treatment of respiratory diseases

2021 ◽  
Vol 30 (161) ◽  
pp. 210042
Author(s):  
Pien A. Goldsteen ◽  
Christina Yoseif ◽  
Amalia M. Dolga ◽  
Reinoud Gosens
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
High Throughput Screening ◽  
Respiratory Diseases ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Human Pluripotent Stem Cells ◽  
Medical Need ◽  
New Chemical Entities

Respiratory diseases are among the leading causes of morbidity and mortality worldwide, representing a major unmet medical need. New chemical entities rarely make it into the clinic to treat respiratory diseases, which is partially due to a lack of adequate predictive disease models and the limited availability of human lung tissues to model respiratory disease. Human pluripotent stem cells (hPSCs) may help fill this gap by serving as a scalable human in vitro model. In addition, human in vitro models of rare genetic mutations can be generated using hPSCs. hPSC-derived epithelial cells and organoids have already shown great potential for the understanding of disease mechanisms, for finding new potential targets by using high-throughput screening platforms, and for personalised treatments. These potentials can also be applied to other hPSC-derived lung cell types in the future. In this review, we will discuss how hPSCs have brought, and may continue to bring, major changes to the field of respiratory diseases by understanding the molecular mechanisms of the pathology and by finding efficient therapeutics.

scholarly journals Epigenetic Manipulation Facilitates the Generation of Skeletal Muscle Cells from Pluripotent Stem Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Tomohiko Akiyama ◽  
Shunichi Wakabayashi ◽  
Atsumi Soma ◽  
Saeko Sato ◽  
Yuhki Nakatake ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Myogenic Differentiation ◽  
Ectopic Expression ◽  
Cell Types ◽  
Culture Conditions ◽  
The Body ◽  
Specific Cell ◽  
Modifying Factors

Human pluripotent stem cells (hPSCs) have the capacity to differentiate into essentially all cell types in the body. Such differentiation can be directed to specific cell types by appropriate cell culture conditions or overexpressing lineage-defining transcription factors (TFs). Especially, for the activation of myogenic program, early studies have shown the effectiveness of enforced expression of TFs associated with myogenic differentiation, such as PAX7 and MYOD1. However, the efficiency of direct differentiation was rather low, most likely due to chromatin features unique to hPSCs, which hinder the access of TFs to genes involved in muscle differentiation. Indeed, recent studies have demonstrated that ectopic expression of epigenetic-modifying factors such as a histone demethylase and an ATP-dependent remodeling factor significantly enhances myogenic differentiation from hPSCs. In this article, we review the recent progress for in vitro generation of skeletal muscles from hPSCs through forced epigenetic and transcriptional manipulation.

scholarly journals Differentiation of Cardiomyocytes from Human Pluripotent Stem Cells Using Monolayer Culture

2015 ◽  
Vol 10s1 ◽  
pp. BMI.S20050 ◽  
Author(s):  
Ivan Batalov ◽  
Adam W. Feinberg
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Heart Development ◽  
Cardiac Tissue ◽  
Cell Types ◽  
Human Pluripotent Stem Cells ◽  
Cardiac Differentiation ◽  
Heart Repair ◽  
External Stimuli

Human pluripotent stem cells (PSCs) are a promising cell source for cardiac tissue engineering and cell-based therapies for heart repair because they can be expanded in vitro and differentiated into most cardiovascular cell types, including cardiomyocytes. During embryonic heart development, this differentiation occurs under the influence of internal and external stimuli that guide cells to go down the cardiac lineage. In order to differentiate PSCs in vitro, these or similar stimuli need to be provided in a controlled manner. However, because it is not possible to completely recapitulate the embryonic environment, the factors essential for cardiac differentiation of PSCs in vitro need to be experimentally determined and validated. Since PSCs were first developed, significant progress has been made in optimizing techniques for their differentiation toward cardiomyocytes. In this review, we will summarize recent advances in these techniques, with particular focus on monolayer-based methods that have improved the efficiency and scalability of cardiomyocyte differentiation.

scholarly journals Generation of mature compact ventricular cardiomyocytes from human pluripotent stem cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shunsuke Funakoshi ◽  
Ian Fernandes ◽  
Olya Mastikhina ◽  
Dan Wilkinson ◽  
Thinh Tran ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Target Population ◽  
Cell Types ◽  
Human Pluripotent Stem Cells ◽  
Differentiation Strategy ◽  
Ventricular Cardiomyocytes ◽  
Ventricular Cells ◽  
Key Aspects

AbstractCompact cardiomyocytes that make up the ventricular wall of the adult heart represent an important therapeutic target population for modeling and treating cardiovascular diseases. Here, we established a differentiation strategy that promotes the specification, proliferation and maturation of compact ventricular cardiomyocytes from human pluripotent stem cells (hPSCs). The cardiomyocytes generated under these conditions display the ability to use fatty acids as an energy source, a high mitochondrial mass, well-defined sarcomere structures and enhanced contraction force. These ventricular cells undergo metabolic changes indicative of those associated with heart failure when challenged in vitro with pathological stimuli and were found to generate grafts consisting of more mature cells than those derived from immature cardiomyocytes following transplantation into infarcted rat hearts. hPSC-derived atrial cardiomyocytes also responded to the maturation cues identified in this study, indicating that the approach is broadly applicable to different subtypes of the heart. Collectively, these findings highlight the power of recapitulating key aspects of embryonic and postnatal development for generating therapeutically relevant cell types from hPSCs.

Evaluating the utility of cardiomyocytes from human pluripotent stem cells for drug screening

2010 ◽  
Vol 38 (4) ◽  
pp. 1037-1045 ◽  
Author(s):  
Emily Dick ◽  
Divya Rajamohan ◽  
Jonathon Ronksley ◽  
Chris Denning
Keyword(s):  
Stem Cells ◽  
Drug Screening ◽  
Pluripotent Stem Cells ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Human Pluripotent Stem Cells ◽  
Attrition Rates ◽  
Human Cardiomyocytes ◽  
Induced Pluripotent

Functional cardiomyocytes can now be derived routinely from hPSCs (human pluripotent stem cells), which collectively include embryonic and induced pluripotent stem cells. This technology presents new opportunities to develop pharmacologically relevant in vitro screens to detect cardiotoxicity, with a view to improving patient safety while reducing the economic burden to industry arising from high drug attrition rates. In the present article, we consider the need for human cardiomyocytes in drug-screening campaigns and review the strategies used to differentiate hPSCs towards the cardiac lineage. During early stages of differentiation, hPSC-cardiomyocytes display gene expression profiles, ultra-structures, ion channel functionality and pharmacological responses reminiscent of an embryonic phenotype, but maturation during extended time in culture has been demonstrated convincingly. Notably, hPSC-cardiomyocytes have been shown to respond in a highly predictable manner to over 40 compounds that have a known pharmacological effect on the human heart. This suggests that further development and validation of the hPSC-cardiomyocyte model as a tool for assessing cardiotoxicity is warranted.

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