Spatial dynamics of feedback and feedforward regulation in cell lineages.
Spatial dynamics of feedback and feedforward regulation in cell lineages.
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DOI：
10.1371/journal.pcbi.1010039
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发表时间：
2022-05
影响因子：
4.3
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中科院分区：
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细胞谱系内的反馈机制被认为是维持组织稳态的重要机制。假设混合良好的细胞群的数学模型和实验数据表明，分化细胞对干细胞自我更新概率的负反馈可以维持稳定的平衡，从而保持体内平衡。然而，细胞谱系动力学的特点是空间结构，这可能导致不同的性质。在这里，我们使用空间明确的计算模型来研究这些动态，包括细胞分裂、分化、死亡和迁移/扩散过程。根据这些模型，在强空间限制和快速迁移/扩散的假设下，干细胞自我更新的负反馈回路无法维持稳态。虽然不能维持体内平衡，但这种反馈可以调节细胞密度，促进模型中空间结构的形成。然而，如果空间限制的自我更新负反馈与实验记录的空间前馈回路相结合，干细胞调节转运扩增细胞的命运，则可以实现组织稳态。这表明组织细胞系中反馈调节的动态比以前认为的更复杂，并且空间显式控制机制的组合可能是有用的。高等生物的组织维持在稳态设定值水平，这是由一套复杂的调节机制决定的。从分化细胞到干细胞分裂模式的负反馈循环，已被实验证明，被认为有助于稳态调节。这部分是基于对数学模型的分析。然而，这些模型通常基于常微分方程，假设细胞和分子完美混合，而在体内，组织具有明显的空间结构特征。在这里，我们表明这种负反馈机制在空间显式计算模型中失去了维持组织稳态的能力。然而，干细胞分裂的负反馈可以导致干细胞和分化细胞组织成不同的，空间分离的岛屿，其中干细胞占细胞群的一小部分。模型中负反馈控制的减少导致这些空间结构的破坏和干细胞的富集。我们进一步表明，如果干细胞分裂的负反馈与其他实验记录的空间明确控制机制相结合，控制回路可以在这种空间环境中维持内稳态，这表明更复杂的控制回路组合是有用的。
Feedback mechanisms within cell lineages are thought to be important for maintaining tissue homeostasis. Mathematical models that assume well-mixed cell populations, together with experimental data, have suggested that negative feedback from differentiated cells on the stem cell self-renewal probability can maintain a stable equilibrium and hence homeostasis. Cell lineage dynamics, however, are characterized by spatial structure, which can lead to different properties. Here, we investigate these dynamics using spatially explicit computational models, including cell division, differentiation, death, and migration / diffusion processes. According to these models, the negative feedback loop on stem cell self-renewal fails to maintain homeostasis, both under the assumption of strong spatial restrictions and fast migration / diffusion. Although homeostasis cannot be maintained, this feedback can regulate cell density and promote the formation of spatial structures in the model. Tissue homeostasis, however, can be achieved if spatially restricted negative feedback on self-renewal is combined with an experimentally documented spatial feedforward loop, in which stem cells regulate the fate of transit amplifying cells. This indicates that the dynamics of feedback regulation in tissue cell lineages are more complex than previously thought, and that combinations of spatially explicit control mechanisms are likely instrumental. Tissues in higher organisms are maintained at a homeostatic setpoint level, which is determined by a complex set of regulatory mechanisms. Negative feedback loops from differentiated cells onto stem cell division patterns, which have been experimentally documented, are thought to contribute to homeostatic regulation. This is in part based on the analysis of mathematical models. Typically, however, such models are based on ordinary differential equations, which assume perfect mixing of cells and molecule, while in vivo, tissues are characterized by pronounced spatial structure. Here, we show that this negative feedback mechanism loses the ability to maintain tissue homeostasis in spatially explicit computational models. Negative feedback on stem cell division, however, can lead to the organization of stem and differentiated cells into distinct, spatially separated islands, where stem cells comprise a small fraction of the cell population. Reduction of negative feedback control in the model results in a breakdown of these spatial structures and stem cell enrichment. We further show that control loops can maintain homeostasis in this spatial setting if the negative feedback on stem cell divisions is combined with other, experimentally documented, spatially explicit control mechanisms, indicating that more complex combinations of control loops are instrumental.