Computational modelling of embryonic stem-cell fate control

Herberg, Maria; Roeder, Ingo

doi:10.1242/dev.116343

Cited by 57 publications

(51 citation statements)

References 88 publications

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“…Bona fide iPSCs are, like murine embryonic stem cells (ESCs), competent to form blastocyst chimaeras and are considered to occupy a state of naïve pluripotency similar to that in the pre-implantation embryo Boroviak et al, 2015). Experimental and computational efforts have led to circuitry mapping of the core TF program that maintains ESC self-renewal under defined conditions (Chen et al, 2008;Niwa et al, 2009;MacArthur et al, 2012;Dunn et al, 2014;Herberg & Roeder, 2015;Rue & Martinez Arias, 2015;Yachie-Kinoshita et al, 2018). Experimental and computational efforts have led to circuitry mapping of the core TF program that maintains ESC self-renewal under defined conditions (Chen et al, 2008;Niwa et al, 2009;MacArthur et al, 2012;Dunn et al, 2014;Herberg & Roeder, 2015;Rue & Martinez Arias, 2015;Yachie-Kinoshita et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…This unique identity is determined by a self-reinforcing interaction network of TFs. Experimental and computational efforts have led to circuitry mapping of the core TF program that maintains ESC self-renewal under defined conditions (Chen et al, 2008;Niwa et al, 2009;MacArthur et al, 2012;Dunn et al, 2014;Herberg & Roeder, 2015;Rue & Martinez Arias, 2015;Yachie-Kinoshita et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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A common molecular logic determines embryonic stem cell self‐renewal and reprogramming

Dunn

Carbognin

et al. 2018

The EMBO Journal

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During differentiation and reprogramming, new cell identities are generated by reconfiguration of gene regulatory networks. Here, we combined automated formal reasoning with experimentation to expose the logic of network activation during induction of naïve pluripotency. We find that a Boolean network architecture defined for maintenance of naïve state embryonic stem cells (ESC) also explains transcription factor behaviour and potency during resetting from primed pluripotency. Computationally identified gene activation trajectories were experimentally substantiated at single‐cell resolution by RT–qPCR. Contingency of factor availability explains the counterintuitive observation that Klf2, which is dispensable for ESC maintenance, is required during resetting. We tested 124 predictions formulated by the dynamic network, finding a predictive accuracy of 77.4%. Finally, we show that this network explains and predicts experimental observations of somatic cell reprogramming. We conclude that a common deterministic program of gene regulation is sufficient to govern maintenance and induction of naïve pluripotency. The tools exemplified here could be broadly applied to delineate dynamic networks underlying cell fate transitions.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A common molecular logic determines embryonic stem cell self‐renewal and reprogramming

Dunn

Carbognin

et al. 2018

The EMBO Journal

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“…In recent years, a number of experimental strategies (reviewed in [25]) and computational models (reviewed in [26]) have been applied to reveal the molecular mechanisms and interactions underlying Nanog heterogeneity. Analysing the dynamic behaviour of small-scale TF network models, we previously identified two potential mechanisms that consistently account for bimodal Nanog distributions and reversible state transitions between different expression levels [22,27].…”

Section: Introductionmentioning

confidence: 99%

Dissecting mechanisms of mouse embryonic stem cells heterogeneity through a model-based analysis of transcription factor dynamics

Herberg

Glauche

Zerjatke

et al. 2016

J. R. Soc. Interface.

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Pluripotent mouse embryonic stem cells (mESCs) show heterogeneous expression levels of transcription factors (TFs) involved in pluripotency regulation, among them Nanog and Rex1. The expression of both TFs can change dynamically between states of high and low activity, correlating with the cells' capacity for self-renewal. Stochastic fluctuations as well as sustained oscillations in gene expression are possible mechanisms to explain this behaviour, but the lack of suitable data hampered their clear distinction. Here, we present a systems biology approach in which novel experimental data on TF heterogeneity is complemented by an agent-based model of mESC self-renewal. Because the model accounts for intracellular interactions, cell divisions and heredity structures, it allows for evaluating the consistency of the proposed mechanisms with data on population growth and on TF dynamics after cell sorting. Our model-based analysis revealed that a bistable, noise-driven network model fulfils the minimal requirements to consistently explain Nanog and Rex1 expression dynamics in heterogeneous and sorted mESC populations. Moreover, we studied the impact of TF-related proliferation capacities on the frequency of state transitions and demonstrate that cellular genealogies can provide insights into the heredity structures of mESCs.

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“…Because genome-wide studies using mouse and human ESCs have revealed the architecture of the gene regulatory network (GRN) responsible for maintaining their selfrenewal and pluripotency, [68][69][70] several computational models describing the mutual regulation of the genes involved in such GRNs have also been developed. 71,72 In those models, stem cell differentiation is described by the transition from stem cell states, in which a set of self-renewal genes are upregulated, to the differentiation states, in which differentiation genes are upregulated and are negatively regulated by the self-renewal genes. Temporal change in the expression of the self-renewal genes in a given GRN can be modeled with multiple approaches, such as Boolean and ODEs.…”

Section: Models For Describing Stem Cell Differentiationmentioning

confidence: 99%

Current state and perspectives in modeling and control of human pluripotent stem cell expansion processes in stirred‐tank bioreactors

Galvanauskas

Grincas

Simutis

et al. 2017

Biotechnology Progress

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Implementation of model-based practices for process development, control, automation, standardization, and validation are important factors for therapeutic and industrial applications of human pluripotent stem cells. As robust cultivation strategies for pluripotent stem cell expansion and differentiation have yet to be determined, process development could be enhanced by application of mathematical models and advanced control systems to optimize growth conditions. Therefore, it is important to understand both the potential of possible applications and the apparent limitations of existing mathematical models to improve pluripotent stem cell cultivation technologies. In the present review, the authors focus on these issues as they apply to stem cell expansion processes. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:355-364, 2017.

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Computational modelling of embryonic stem-cell fate control

Cited by 57 publications

References 88 publications

A common molecular logic determines embryonic stem cell self‐renewal and reprogramming

A common molecular logic determines embryonic stem cell self‐renewal and reprogramming

Dissecting mechanisms of mouse embryonic stem cells heterogeneity through a model-based analysis of transcription factor dynamics

Current state and perspectives in modeling and control of human pluripotent stem cell expansion processes in stirred‐tank bioreactors

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