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Theoretical modeling of trail formation of a migrating neutrophil on substrate

中性粒细胞在基底上迁移过程中曳尾形成的理论模型

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Abstract

Neutrophils undergo fast migration dynamics onto endothelium or extracellular matrix using anterior protrusion together with posterior contraction and retraction. While these migrating cells tend to leave behind the long-lasting membranous trails with enriched integrins ripped down from cell body, it is still unclear how the trail formation is quantitatively correlated with cell migration and what the regulating factors are key in this process. Here a multi-layered mechanochemical model was integrated with a motor-clutch model to simulate numerically the chemotactic migration of a neutrophil on the substrate. Results indicated that, in response to those polarized distributions of sensing molecule P21-activated kinase 1 (PAK1) and the downstream molecules Ras-related C3 botulinum toxin substrate (Rac) and Ras homolog family member (RhoA), membrane-bound integrins tend to be accumulated at both the cell front and rear, promoting the increase of migrating velocity and trail number with time when actin-related protein2/3 complex (Arp2/3) and myosin are respectively accumulated at the front and rear. These predictions were in agreement with those typical experimental observations in integrin polarization and trail formation. Parametric analysis further proposed that, while the migrating velocity yields a biphasic dependence on substrate hardness and motor unloaded velocity, trail number increases monotonically with substrate hardness, on-rate of integrin-ligand bonds, motor unloaded velocity, motor stall force, and clutch number but decreases with chemokine concentration and off-rate of integrin-ligand bonds. This work provided an insight in elaborating the mechanochemical pathways in neutrophil migration and deciphering the key extracellular or intracellular factors in regulating the relevant trail formation of those migrating neutrophils.

摘要

中性粒细胞通过头部前伸和尾部收缩可以在内皮细胞或细胞外基质上快速迁移. 这些细胞在迁移的过程中会遗留下大量富含 整合素的膜结构, 但目前尚不清楚曳尾的形成与细胞迁移之间的定量关系以及在这一过程中起关键作用的调控因素. 本文将多层级力 学-化学耦合模型与细胞迁移的马达-离合器模型相结合, 对中性粒细胞在基质上的趋化迁移进行了数值模拟. 结果表明, 随着PAK1和 其下游信号分子Rac和RhoA的极化分布, 细胞膜上的整合素倾向于在细胞前后两端产生极化积聚, 当Arp2/3和myosin分别在细胞的头 尾极化时, 细胞会在整合素的作用下增大迁移速度并提高曳尾的数量. 这些关于整合素极化以及曳尾形成的预测与典型的实验结果一 致. 参数分析进一步表明, 虽然细胞迁移速度与基底硬度和“马达”空载速度呈现双相依赖关系, 但是曳尾形成的数量随着基底硬度、整 合素-配体分子键的结合率、“马达”空载速度、“马达”空载拉力和“离合器”数量的增加而单调增加, 随着趋化因子浓度和整合素-配体 分子键的解离率的增加而减少. 上述工作为阐明中性粒细胞迁移的力学-化学-生物学耦合过程和探究调节中性粒细胞迁移过程中影响 曳尾形成的关键因素提供了一种解释.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant Nos. 31627804, 11772345, and 91539119), the Scientific Instrument Developing Project of the Chinese Academy of Sciences (Grant No. GJJSTU20220002), and Frontier Science Key Project of Chinese Science Academy (Grant No. QYZDJ-SSW-JSC018).

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Authors and Affiliations

  1. Center for Biomechanics and Bioengineering, Beijing Key Laboratory of Engineered Construction and Mechanobiology and Key Laboratory of Microgravity (National Microgravity Laboratory), Institute of Mechanics, Chinese Academy of Sciences, Beijing, 100190, China

    Xiaoning Zhang  (张晓宁), Wenhui Hu  (胡文慧), Wenbo Gao  (高文博), Yan Zhang  (章燕) & Mian Long  (龙勉)

  2. School of Engineering Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China

    Xiaoning Zhang  (张晓宁), Yan Zhang  (章燕) & Mian Long  (龙勉)

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  1. Xiaoning Zhang  (张晓宁)
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  2. Wenhui Hu  (胡文慧)
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  3. Wenbo Gao  (高文博)
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  4. Yan Zhang  (章燕)
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Contributions

Xiaoning Zhang, Yan Zhang, and Mian Long developed the concept, designed the simulations, analyzed the data, wrote the paper, revised and edited the final version. Xiaoning Zhang developed mathematical model and conducted numerical simulations. Wenhui Hu and Wenbo Gao performed experiments.

Corresponding authors

Correspondence to Yan Zhang  (章燕) or Mian Long  (龙勉).

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Zhang, X., Hu, W., Gao, W. et al. Theoretical modeling of trail formation of a migrating neutrophil on substrate. Acta Mech. Sin. 39, 622461 (2023). https://doi.org/10.1007/s10409-023-22461-x

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  • DOI: https://doi.org/10.1007/s10409-023-22461-x

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