Awakening the HSC: Dynamic Modeling of HSC Maintenance Unravels Regulation of the TP53 Pathway and Quiescence
Open Access
- 31 July 2020
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Physiology
- Vol. 11, 848
- https://doi.org/10.3389/fphys.2020.00848
Abstract
Hematopoietic stem cells (HSCs) provide all types of blood cells during the entire life of the organism. HSCs are mainly quiescent and can eventually enter the cell cycle to differentiate. HSCs are maintained and tightly regulated in a particular environment. The stem cell niche regulates dormancy and awakening. Deregulations of this interplay can lead to hematopoietic failure and diseases. In this paper, we present a Boolean network model that recapitulates HSC regulation in virtue of external signals coming from the niche. This Boolean network integrates and summarizes the current knowledge of HSC regulation and is based on extensive literature research. Furthermore, dynamic simulations suggest a novel systemic regulation of TP53 in homeostasis. Thereby, our model indicates that TP53 activity is balanced depending on external stimulations, engaging a regulatory mechanism involving ROS regulators and RAS activated transcription factors. Finally, we investigated different mouse models and compared them toin silicoknockout simulations. Here, the model could recapitulatein vivoobserved behaviors and thus sustains our results.Keywords
Funding Information
- Bundesministerium für Bildung und Forschung
- Deutsche Forschungsgemeinschaft (217328187)
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