Factors Regulating Pluripotency and Differentiation in Early Mammalian Embryos and Embryo-derived Stem Cells

Suwińska, Aneta; Ciemerych, Maria A.

doi:10.1016/b978-0-12-386015-6.00022-6

Cited by 13 publications

(11 citation statements)

References 187 publications

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“…LIF [15]–[17], BMP-4 [15]) and factors that can initiate differentiation (e.g. Activin A [18], FGF-2 [18], and retinoic acid [19]) have been thoroughly examined, both in terms of the appropriate doses and their temporal administration. In many cases, the signaling pathways and modes of action of these growth factors are also known but the effects of combinatorial treatments can be difficult to predict a priori [16], [20].…”

Section: Introductionmentioning

confidence: 99%

Spatial Pattern Dynamics of 3D Stem Cell Loss of Pluripotency via Rules-Based Computational Modeling

et al. 2013

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Pluripotent embryonic stem cells (ESCs) have the unique ability to differentiate into cells from all germ lineages, making them a potentially robust cell source for regenerative medicine therapies, but difficulties in predicting and controlling ESC differentiation currently limit the development of therapies and applications from such cells. A common approach to induce the differentiation of ESCs in vitro is via the formation of multicellular aggregates known as embryoid bodies (EBs), yet cell fate specification within EBs is generally considered an ill-defined and poorly controlled process. Thus, the objective of this study was to use rules-based cellular modeling to provide insight into which processes influence initial cell fate transitions in 3-dimensional microenvironments. Mouse embryonic stem cells (D3 cell line) were differentiated to examine the temporal and spatial patterns associated with loss of pluripotency as measured through Oct4 expression. Global properties of the multicellular aggregates were accurately recapitulated by a physics-based aggregation simulation when compared to experimentally measured physical parameters of EBs. Oct4 expression patterns were analyzed by confocal microscopy over time and compared to simulated trajectories of EB patterns. The simulations demonstrated that loss of Oct4 can be modeled as a binary process, and that associated patterns can be explained by a set of simple rules that combine baseline stochasticity with intercellular communication. Competing influences between Oct4+ and Oct4− neighbors result in the observed patterns of pluripotency loss within EBs, establishing the utility of rules-based modeling for hypothesis generation of underlying ESC differentiation processes. Importantly, the results indicate that the rules dominate the emergence of patterns independent of EB structure, size, or cell division. In combination with strategies to engineer cellular microenvironments, this type of modeling approach is a powerful tool to predict stem cell behavior under a number of culture conditions that emulate characteristics of 3D stem cell niches.

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Section: Introductionmentioning

confidence: 99%

Spatial Pattern Dynamics of 3D Stem Cell Loss of Pluripotency via Rules-Based Computational Modeling

et al. 2013

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“…Cell cycle arrest in G1 is thought to be permissive for differentiation in ESCs, whereas it is associated with maintenance of stemness in adult stem cells [3][4][5] . Functional differences in the cell cycle machinery of hESCs in comparison to adult stem cells and ESCs and epiblast stem cells (EpiSCs) from other species are known but not fully understood 6 . A major regulator of cell cycle progression in mammalian cells is the RB pathway.…”

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confidence: 99%

The RB family is required for the self-renewal and survival of human embryonic stem cells

2012

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The mechanisms ensuring the long-term self-renewal of human embryonic stem cells are still only partly understood, limiting their use in cellular therapies. Here we found that increased activity of the RB cell cycle inhibitor in human embryonic stem cells induces cell cycle arrest, differentiation and cell death. Conversely, inactivation of the entire RB family (RB, p107 and p130) in human embryonic stem cells triggers G2/M arrest and cell death through functional activation of the p53 pathway and the cell cycle inhibitor p21. Differences in E2F target gene activation upon loss of RB family function between human embryonic stem cells, mouse embryonic stem cells and human fibroblasts underscore key differences in the cell cycle regulatory networks of human embryonic stem cells. Finally, loss of RB family function promotes genomic instability in both human and mouse embryonic stem cells, uncoupling cell cycle defects from chromosomal instability. These experiments indicate that a homeostatic level of RB activity is essential for the self-renewal and the survival of human embryonic stem cells.

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“…Although there are similar spatio-temporal expression patterns in various species, genes with significantly different expressive features are the focus of the researchers. For example, POU5F1 is a key factor for embryonic development and stem cell pluripotency [40,41], the expression of which rapidly increases at the four-cell stage in humans and mouse. On the contrary, it smoothly expresses in other species.…”

Section: Resultsmentioning

confidence: 99%

EmExplorer: a database for exploring time activation of gene expression in mammalian embryos

Zheng

Long

et al. 2019

Open Biol.

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Understanding early development offers a striking opportunity to investigate genetic disease, stem cell and assisted reproductive technology. Recent advances in high-throughput sequencing technology have led to the rising influx of omics data, which have rapidly boosted our understanding of mammalian developmental mechanisms. Here, we review the database EmExplorer (a database for exploring time activation of gene expression in mammalian embryos), which systematically organizes the genes from development-related pathways, and which we have already established and continue to update it. The current version of EmExplorer incorporates over 26 000 genes obtained from 306 functional pathways in five species. The function annotations of development-related genes were also integrated into EmExplorer. To facilitate data extraction, the database also contains the following information. (i) The dynamic expression values for each development stage are matched to the corresponding genes. (ii) A two-layer search tool which supports multi-option searching, such as by official symbol, pathway name and function annotation. The returned entries can directly link to the analysis results for the corresponding gene or pathway in the analysis module. (iii) The analysis module provides different gene comparisons at the multi-species level and functional pathway level, which shows the species specificity and stage specificity at the gene or pathway level. (iv) The analysis based on the hypergeometric distribution test reveals the enrichment of gene functions at a particular stage of one organism's pathway. (v) The browser is designed for users with ambiguous searching goals and greatly helps new users to get a general idea of the contents of the database. (vi) The experimentally validated pathways are manually curated and shown on the home page. EmExplorer will be helpful for elucidating early developmental mechanisms and exploring time activation genes. EmExplorer is freely available at http://bioinfor.imu.edu.cn/emexplorer .

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Factors Regulating Pluripotency and Differentiation in Early Mammalian Embryos and Embryo-derived Stem Cells

Cited by 13 publications

References 187 publications

Spatial Pattern Dynamics of 3D Stem Cell Loss of Pluripotency via Rules-Based Computational Modeling

Spatial Pattern Dynamics of 3D Stem Cell Loss of Pluripotency via Rules-Based Computational Modeling

The RB family is required for the self-renewal and survival of human embryonic stem cells

EmExplorer: a database for exploring time activation of gene expression in mammalian embryos

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