A system-level model reveals that transcriptional stochasticity is required for hematopoietic stem cell differentiation

• Published in: NPJ systems biology and applications Vol. 10; no. 1; pp. 145 - 21
• Main Authors: Herrera, Joel, Bensussen, Antonio, García-Gómez, Mónica L., Garay-Arroyo, Adriana, Álvarez-Buylla, Elena R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.12.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/136/532; 631/449; Adipocytes; Animals; Bioinformatics; Biology; Biomedical and Life Sciences; Bone marrow; Boolean; Cell culture; Cell cycle; Cell differentiation; Cell Differentiation - genetics; Cell Differentiation - physiology; Computational Biology/Bioinformatics; Computer Appl. in Life Sciences; Dendritic cells; Gene expression; Gene Regulatory Networks - genetics; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humans; Hypoxia; Life Sciences; Metabolism; Metabolites; Models, Biological; Neutrophils; Phosphorylation; Physiology; Reactive oxygen species; Reactive Oxygen Species - metabolism; Signal Transduction - genetics; Signal Transduction - physiology; Stem cells; Stochastic Processes; Stochasticity; Systems Biology; Systems Biology - methods; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2056-7189; 2056-7189
• DOI: 10.1038/s41540-024-00469-8

HSCs differentiation has been difficult to study experimentally due to the high number of components and interactions involved, as well as the impact of diverse physiological conditions. From a 200-node network, that was grounded on experimental data, we derived a 21-node regulatory network by collapsing linear pathways and retaining the functional feedback loops. This regulatory network core integrates key nodes and interactions underlying HSCs differentiation, including transcription factors, metabolic, and redox signaling pathways. We used Boolean, continuous, and stochastic dynamic models to simulate the hypoxic conditions of the HSCs niche, as well as the patterns and temporal sequences of HSCs transitions and differentiation. Our findings indicate that HSCs differentiation is a plastic process in which cell fates can transdifferentiate among themselves. Additionally, we found that cell heterogeneity is fundamental for HSCs differentiation. Lastly, we found that oxygen activates ROS production, inhibiting quiescence and promoting growth and differentiation pathways of HSCs.