Awakening the HSC: Dynamic Modeling of HSC Maintenance Unravels Regulation of the TP53 Pathway and Quiescence
| Autor: | Ikonomi, Nensi, Kühlwein, Silke D., Schwab, Julian D., Kestler, Hans A. |
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| Rok vydání: | 2020 |
| Předmět: |
Hom��ostase
Physiology Boolean network lcsh:Physiology Algebra Boolean dynamic modeling ddc:570 homeostasis niche interactions Homeostasis ddc:610 Maintenance of quiescence TP53 stem cell awakening p53 protein Boolesches Modell Homöostase Original Research lcsh:QP1-981 Genes p53 Stem cell awakening maintenance of quiescence Niche interactions Blutstammzelle Boolesches Netz hematopoietic stem cell DDC 610 / Medicine & health Hematopoietic stem cells Dynamic modeling |
| Zdroj: | Frontiers in Physiology, Vol 11 (2020) Frontiers in Physiology |
| ISSN: | 1664-042X |
| Popis: | 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 to in silico knockout simulations. Here, the model could recapitulate in vivo observed behaviors and thus sustains our results. publishedVersion |
| Databáze: | OpenAIRE |
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