A major next step in hematopoietic stem cell (HSC) biology is to enhance our quantitative understanding of cellular and evolutionary dynamics involved in undisturbed hematopoiesis. Mathematical models have been and continue to be key in this respect, and are most powerful when parameterized experimentally and containing sufficient biological complexity. In this paper, we use data from label propagation experiments in mice to parameterize a mathematical model of hematopoiesis that includes homeostatic control mechanisms as well as clonal evolution. We find that nonlinear feedback control can drastically change the interpretation of kinetic estimates at homeostasis. This suggests that short-term HSC and multipotent progenitors can dynamically adjust to sustain themselves temporarily in the absence of long-term HSCs, even if they differentiate more often than they self-renew in undisturbed homeostasis. Additionally, the presence of feedback control in the model renders the system resilient against mutant invasion. Invasion barriers, however, can be overcome by a combination of age-related changes in stem cell differentiation and evolutionary niche construction dynamics based on a mutant-associated inflammatory environment. This helps us understand the evolution of e.g., TET2 or DNMT3A mutants, and how to potentially reduce mutant burden.

中文翻译：

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实验参数化数学模型揭示了稳态造血过程中动态调整的细胞命运决定和对突变体入侵的抵抗力


造血干细胞（HSC）生物学的下一步重要步骤是增强我们对未受干扰的造血作用所涉及的细胞和进化动力学的定量理解。数学模型在这方面一直并将继续发挥关键作用，并且在通过实验参数化并包含足够的生物复杂性时最为强大。在本文中，我们使用小鼠标签传播实验的数据来参数化造血数学模型，其中包括稳态控制机制以及克隆进化。我们发现非线性反馈控制可以极大地改变稳态动力学估计的解释。这表明短期 HSC 和多能祖细胞可以动态调整以在缺乏长期 HSC 的情况下暂时维持自身，即使它们在不受干扰的体内平衡中分化比自我更新更频繁。此外，模型中反馈控制的存在使系统能够抵抗突变体入侵。然而，可以通过干细胞分化的年龄相关变化和基于突变相关炎症环境的进化生态位构建动力学的组合来克服侵袭障碍。这有助于我们了解 TET2 或 DNMT3A 突变体的进化，以及如何潜在地减少突变体负担。