Embryonic stem cell application in drug discovery

Lou, Yijia; Liang, Xiaoyang

doi:10.1038/aps.2010.194

Cited by 14 publications

(7 citation statements)

References 62 publications

(117 reference statements)

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“…Some applications require clonal homogeneous populations, e.g. drug discovery 9 and iPSCs for personalised medicine. The selection of the best clones for further experimentation needs to be optimised to make clinical applications safe.…”

Section: Introductionmentioning

confidence: 99%

Seeding hESCs to achieve optimal colony clonality

Wadkin

Orozco-Fuentes

Neganova

et al. 2019

Sci Rep

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Human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) have promising clinical applications which often rely on clonally-homogeneous cell populations. To achieve this, it is important to ensure that each colony originates from a single founding cell and to avoid subsequent merging of colonies during their growth. Clonal homogeneity can be obtained with low seeding densities; however, this leads to low yield and viability. It is therefore important to quantitatively assess how seeding density affects clonality loss so that experimental protocols can be optimised to meet the required standards. Here we develop a quantitative framework for modelling the growth of hESC colonies from a given seeding density based on stochastic exponential growth. This allows us to identify the timescales for colony merges and over which colony size no longer predicts the number of founding cells. We demonstrate the success of our model by applying it to our own experiments of hESC colony growth; while this is based on a particular experimental set-up, the model can be applied more generally to other cell lines and experimental conditions to predict these important timescales.

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Section: Introductionmentioning

confidence: 99%

Seeding hESCs to achieve optimal colony clonality

Wadkin

Orozco-Fuentes

Neganova

et al. 2019

Sci Rep

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“…Investigation on the response of ES cells to SMG will help us understand the effect of MG on the reproduction system and embryonic development. Nowadays, ES cells and their differentiated progeny offer tremendous potential for regenerative medicine [15] . In addition, the usage of rotary microgravity clinostats as bioreactors to provide clinically relevant numbers of homogenous therapeutic cell populations for stem-cell-based therapies, especially in the field of ES-derived lineage-specific stem cell induction has aroused much attention [16] , [17] , [18] .…”

Section: Introductionmentioning

confidence: 99%

Effects of Simulated Microgravity on Embryonic Stem Cells

Wang

Jiang

et al. 2011

PLoS ONE

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There have been many studies on the biological effects of simulated microgravity (SMG) on differentiated cells or adult stem cells. However, there has been no systematic study on the effects of SMG on embryonic stem (ES) cells. In this study, we investigated various effects (including cell proliferation, cell cycle distribution, cell differentiation, cell adhesion, apoptosis, genomic integrity and DNA damage repair) of SMG on mouse embryonic stem (mES) cells. Mouse ES cells cultured under SMG condition had a significantly reduced total cell number compared with cells cultured under 1 g gravity (1G) condition. However, there was no significant difference in cell cycle distribution between SMG and 1G culture conditions, indicating that cell proliferation was not impaired significantly by SMG and was not a major factor contributing to the total cell number reduction. In contrast, a lower adhesion rate cultured under SMG condition contributed to the lower cell number in SMG. Our results also revealed that SMG alone could not induce DNA damage in mES cells while it could affect the repair of radiation-induced DNA lesions of mES cells. Taken together, mES cells were sensitive to SMG and the major alterations in cellular events were cell number expansion, adhesion rate decrease, increased apoptosis and delayed DNA repair progression, which are distinct from the responses of other types of cells to SMG.

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“…ESCs (identified through preimplantion genetic diagnosis), and iPSCs in particular [44][45][46], can resolve some of the limitations mentioned in the previous section by their ability to be disease and patient specific, the decrease in the cost of deriving such lines, and the concerted effort to make wellcharacterized lines widely available. Since iPSCs can be differentiated into most cell types (or cocultures consisting of multiple cell types) to investigate healthy and disease processes in a cell-type-specific manner, one can assess the effect of a gene or an allelic background in thoughtfully selected mix-and-match experiments (see eg, Xu et al [47]).…”

Section: How Ipscs Can Enhance the Utility Of In Vitro Models Of Diseasementioning

confidence: 99%

Induced Pluripotent Stem Cell Models to Enable In Vitro Models for Screening in the Central Nervous System

Hunsberger

Efthymiou

Malik

et al. 2015

Stem Cells and Development

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There is great need to develop more predictive drug discovery tools to identify new therapies to treat diseases of the central nervous system (CNS). Current nonpluripotent stem cell-based models often utilize non-CNS immortalized cell lines and do not enable the development of personalized models of disease. In this review, we discuss why in vitro models are necessary for translational research and outline the unique advantages of induced pluripotent stem cell (iPSC)-based models over those of current systems. We suggest that iPSC-based models can be patient specific and isogenic lines can be differentiated into many neural cell types for detailed comparisons. iPSC-derived cells can be combined to form small organoids, or large panels of lines can be developed that enable new forms of analysis. iPSC and embryonic stem cell-derived cells can be readily engineered to develop reporters for lineage studies or mechanism of action experiments further extending the utility of iPSC-based systems. We conclude by describing novel technologies that include strategies for the development of diversity panels, novel genomic engineering tools, new three-dimensional organoid systems, and modified high-content screens that may bring toxicology into the 21st century. The strategic integration of these technologies with the advantages of iPSC-derived cell technology, we believe, will be a paradigm shift for toxicology and drug discovery efforts.Disease Modeling D iseases of the central nervous system (CNS) affect a large number of people, but therapeutic intervention is hampered by the lack of useful models for many of these diseases. Current research on human subjects, particularly for drug discovery for CNS diseases, is severely (and appropriately) limited by ethical guidelines. Therefore, surrogate models are needed that share important anatomical, physiological, and genetic features to advance new treatments and therapies for CNS diseases [1].Developing rapid and effective therapies for CNS diseases requires the availability of in vitro models that accurately recapitulate disease phenotypes and predict patient treatment response. A proper model must be both sensitive and predictive while reflecting both normal and disease processes. Equally important, these models should enable the investigation of genetic and environmental risk factors contributing to diseases in a rapid and economical way. Currently used models often do not reflect a typical human response [2-4], despite efforts underway to better characterize these models and increase their preclinical value in predicting safety and efficacy in the clinic [5,6]. Therefore, there is a great need to develop disease-and patient-specific models from cells directly affected in CNS disorders. These cellbased models, we envision, could either replace or supplement current animal models and enable the efficient translation of basic research into the clinical setting. Limitations with current CNS modelsCurrently, drug discovery relies on the use of animalbased or cell-based models, ...

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Embryonic stem cell application in drug discovery

Cited by 14 publications

References 62 publications

Seeding hESCs to achieve optimal colony clonality

Seeding hESCs to achieve optimal colony clonality

Effects of Simulated Microgravity on Embryonic Stem Cells

Induced Pluripotent Stem Cell Models to Enable In Vitro Models for Screening in the Central Nervous System

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