scholarly journals Population-based mechanistic modeling allows for quantitative predictions of drug responses across cell types

2017 ◽  
Author(s):  
Jingqi QX Gong ◽  
Eric A Sobie
Keyword(s):  
Pluripotent Stem Cells ◽  
Cardiac Electrophysiology ◽  
Cell Types ◽  
Population Based ◽  
Experimental Models ◽  
Mechanistic Modeling ◽  
Type Model ◽  
Cell Type ◽  
Drug Responses ◽  
Induced Pluripotent

ABSTRACTQuantitative mismatches between human physiology and experimental models can present serious limitations for the development of effective therapeutics. We addressed this issue, in the context of cardiac electrophysiology, through mechanistic mathematical modeling combined with statistical analyses. Physiological metrics were simulated in heterogeneous populations describing cardiac myocytes from adult ventricles and those derived from induced pluripotent stem cells (iPSC-CMs). These simulated measures were used to construct a cross-cell type regression model that predicts adult myocyte drug responses from iPSC-CM behaviors. We found that quantitatively accurate predictions of responses to selective or non-selective drugs could be generated based on iPSC-CM responses and that the method can be extended to predict drug responses in diseased as well as healthy cells. This cross-cell type model can be of great value in drug development, and the approach, which can be applied to other fields, represents an important strategy for overcoming experimental model limitations.

scholarly journals A Web-Server of Cell Type Discrimination System

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Anyou Wang ◽  
Yan Zhong ◽  
Yanhua Wang ◽  
Qianchuan He
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Embryonic Stem ◽  
Web Server ◽  
Cell Types ◽  
Cell Type ◽  
User Input ◽  
The Common ◽  
Induced Pluripotent ◽  
User Friendly

Discriminating cell types is a daily request for stem cell biologists. However, there is not a user-friendly system available to date for public users to discriminate the common cell types, embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and somatic cells (SCs). Here, we develop WCTDS, a web-server of cell type discrimination system, to discriminate the three cell types and their subtypes like fetal versus adult SCs. WCTDS is developed as a top layer application of our recent publication regarding cell type discriminations, which employs DNA-methylation as biomarkers and machine learning models to discriminate cell types. Implemented by Django, Python, R, and Linux shell programming, run under Linux-Apache web server, and communicated through MySQL, WCTDS provides a friendly framework to efficiently receive the user input and to run mathematical models for analyzing data and then to present results to users. This framework is flexible and easy to be expended for other applications. Therefore, WCTDS works as a user-friendly framework to discriminate cell types and subtypes and it can also be expended to detect other cell types like cancer cells.

scholarly journals Cell type determination for cardiac differentiation occurs soon after seeding of human induced pluripotent stem cells

2021 ◽  
Author(s):  
Connie L Jiang ◽  
Yogesh Goyal ◽  
Naveen Jain ◽  
Qiaohong Wang ◽  
Rachel E Truitt ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Cell Types ◽  
Cardiac Differentiation ◽  
Marker Genes ◽  
Directed Differentiation ◽  
Cell Type ◽  
Differentiated Cells ◽  
Induced Pluripotent

Cardiac directed differentiation of human induced pluripotent stem cells consistently produces a mixed population of cardiomyocytes and non-cardiac cell types even when using very well-characterized protocols. We wondered whether differentiated cell types might result from intrinsic differences in hiPS cells prior to the onset of differentiation. By associating individual differentiated cells that share a common hiPS cell precursor, we were able to test whether expression variability in differentiated cells was pre-determined from the hiPS cell state. Although within a single experiment, differentiated cells that share an hiPS cell progenitor were more transcriptionally similar to each other than to other cells in the differentiated population, when the same hiPS cells were differentiated in parallel, we did not observe high transcriptional similarity across differentiations. Additionally, we found that substantial cell death occurred during differentiation in a manner that suggested that all cells were equally likely to survive or die, suggesting that there was no intrinsic selection bias for cells descended from particular hiPS cell progenitors. These results led us to wonder about how cells grow out spatially during the directed differentiation process. Labeling cells by their expression of a few canonical cell type marker genes, we showed that cells expressing the same marker tended to occur in patches observable by visual inspection, suggesting that cell type determination across multiple cell types, once initiated, is maintained in a cell-autonomous manner for multiple divisions. Altogether, our results show that while there is substantial heterogeneity in the initial hiPS cell population, that heterogeneity is not responsible for heterogeneous outcomes, and that the window during which cell type specification occurs is likely to begin shortly after the seeding of hiPS cells for differentiation.

scholarly journals Single cell eQTL analysis identifies cell type-specific genetic control of gene expression in fibroblasts and reprogrammed induced pluripotent stem cells

2020 ◽  
Author(s):  
Drew Neavin ◽  
Quan Nguyen ◽  
Maciej S. Daniszewski ◽  
Helena H. Liang ◽  
Han Sheng Chiu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Single Cell ◽  
Pluripotent Stem Cells ◽  
Cell Types ◽  
Cell Type ◽  
Single Cell Rna Sequencing ◽  
Cell Type Specific ◽  
Induced Pluripotent

AbstractThe discovery that somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) - cells that can be differentiated into any cell type of the three germ layers - has provided a foundation for in vitro human disease modelling1,2, drug development1,2, and population genetics studies3,4. In the majority of instances, the expression levels of genes, plays a critical role in contributing to disease risk, or the ability to identify therapeutic targets. However, while the effect of the genetic background of cell lines has been shown to strongly influence gene expression, the effect has not been evaluated at the level of individual cells. Differences in the effect of genetic variation on the gene expression of different cell-types, would provide significant resolution for in vitro research using preprogramed cells. By bringing together single cell RNA sequencing15–21 and population genetics, we now have a framework in which to evaluate the cell-types specific effects of genetic variation on gene expression. Here, we performed single cell RNA-sequencing on 64,018 fibroblasts from 79 donors and we mapped expression quantitative trait loci (eQTL) at the level of individual cell types. We demonstrate that the large majority of eQTL detected in fibroblasts are specific to an individual sub-type of cells. To address if the allelic effects on gene expression are dynamic across cell reprogramming, we generated scRNA-seq data in 19,967 iPSCs from 31 reprogramed donor lines. We again identify highly cell type specific eQTL in iPSCs, and show that that the eQTL in fibroblasts are almost entirely disappear during reprogramming. This work provides an atlas of how genetic variation influences gene expression across cell subtypes, and provided evidence for patterns of genetic architecture that lead to cell-types specific eQTL effects.

scholarly journals Epigenetic reprogramming of cell identity: lessons from development for regenerative medicine

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Amitava Basu ◽  
Vijay K. Tiwari
Keyword(s):  
Regenerative Medicine ◽  
Cell Types ◽  
Direct Conversion ◽  
Cellular Reprogramming ◽  
Specific Cell ◽  
Cell Type ◽  
Pathological Conditions ◽  
Gene Regulatory ◽  
Induced Pluripotent ◽  
And Function

AbstractEpigenetic mechanisms are known to define cell-type identity and function. Hence, reprogramming of one cell type into another essentially requires a rewiring of the underlying epigenome. Cellular reprogramming can convert somatic cells to induced pluripotent stem cells (iPSCs) that can be directed to differentiate to specific cell types. Trans-differentiation or direct reprogramming, on the other hand, involves the direct conversion of one cell type into another. In this review, we highlight how gene regulatory mechanisms identified to be critical for developmental processes were successfully used for cellular reprogramming of various cell types. We also discuss how the therapeutic use of the reprogrammed cells is beginning to revolutionize the field of regenerative medicine particularly in the repair and regeneration of damaged tissue and organs arising from pathological conditions or accidents. Lastly, we highlight some key challenges hindering the application of cellular reprogramming for therapeutic purposes.

scholarly journals Utilising Induced Pluripotent Stem Cells in Neurodegenerative Disease Research: Focus on Glia

2021 ◽  
Vol 22 (9) ◽  
pp. 4334
Author(s):  
Katrina Albert ◽  
Jonna Niskanen ◽  
Sara Kälvälä ◽  
Šárka Lehtonen
Keyword(s):  
Stem Cells ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Induced Pluripotent Stem Cells ◽  
Glial Cells ◽  
Pluripotent Stem Cells ◽  
Cell Types ◽  
Human Ipscs ◽  
Induced Pluripotent

Induced pluripotent stem cells (iPSCs) are a self-renewable pool of cells derived from an organism’s somatic cells. These can then be programmed to other cell types, including neurons. Use of iPSCs in research has been two-fold as they have been used for human disease modelling as well as for the possibility to generate new therapies. Particularly in complex human diseases, such as neurodegenerative diseases, iPSCs can give advantages over traditional animal models in that they more accurately represent the human genome. Additionally, patient-derived cells can be modified using gene editing technology and further transplanted to the brain. Glial cells have recently become important avenues of research in the field of neurodegenerative diseases, for example, in Alzheimer’s disease and Parkinson’s disease. This review focuses on using glial cells (astrocytes, microglia, and oligodendrocytes) derived from human iPSCs in order to give a better understanding of how these cells contribute to neurodegenerative disease pathology. Using glia iPSCs in in vitro cell culture, cerebral organoids, and intracranial transplantation may give us future insight into both more accurate models and disease-modifying therapies.

scholarly journals A non-invasive method to generate induced pluripotent stem cells from primate urine

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Johanna Geuder ◽  
Lucas E. Wange ◽  
Aleksandar Janjic ◽  
Jessica Radmer ◽  
Philipp Janssen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Sendai Virus ◽  
Cell Types ◽  
Urine Samples ◽  
Comparative Approach ◽  
Non Invasive ◽  
Human Ipscs ◽  
Induced Pluripotent

AbstractComparing the molecular and cellular properties among primates is crucial to better understand human evolution and biology. However, it is difficult or ethically impossible to collect matched tissues from many primates, especially during development. An alternative is to model different cell types and their development using induced pluripotent stem cells (iPSCs). These can be generated from many tissue sources, but non-invasive sampling would decisively broaden the spectrum of non-human primates that can be investigated. Here, we report the generation of primate iPSCs from urine samples. We first validate and optimize the procedure using human urine samples and show that suspension- Sendai Virus transduction of reprogramming factors into urinary cells efficiently generates integration-free iPSCs, which maintain their pluripotency under feeder-free culture conditions. We demonstrate that this method is also applicable to gorilla and orangutan urinary cells isolated from a non-sterile zoo floor. We characterize the urinary cells, iPSCs and derived neural progenitor cells using karyotyping, immunohistochemistry, differentiation assays and RNA-sequencing. We show that the urine-derived human iPSCs are indistinguishable from well characterized PBMC-derived human iPSCs and that the gorilla and orangutan iPSCs are well comparable to the human iPSCs. In summary, this study introduces a novel and efficient approach to non-invasively generate iPSCs from primate urine. This will extend the zoo of species available for a comparative approach to molecular and cellular phenotypes.

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