Wolfson Centre for Mathematical Biology, Oxford University, Oxford, United Kingdom.
Children's Mercy Kansas City, Kansas City, United States.
Elife. 2023 Apr 19;12:e83792. doi: 10.7554/eLife.83792.
Collective cell migration plays an essential role in vertebrate development, yet the extent to which dynamically changing microenvironments influence this phenomenon remains unclear. Observations of the distribution of the extracellular matrix (ECM) component fibronectin during the migration of loosely connected neural crest cells (NCCs) lead us to hypothesize that NCC remodeling of an initially punctate ECM creates a scaffold for trailing cells, enabling them to form robust and coherent stream patterns. We evaluate this idea in a theoretical setting by developing an individual-based computational model that incorporates reciprocal interactions between NCCs and their ECM. ECM remodeling, haptotaxis, contact guidance, and cell-cell repulsion are sufficient for cells to establish streams in silico, however, additional mechanisms, such as chemotaxis, are required to consistently guide cells along the correct target corridor. Further model investigations imply that contact guidance and differential cell-cell repulsion between leader and follower cells are key contributors to robust collective cell migration by preventing stream breakage. Global sensitivity analysis and simulated gain- and loss-of-function experiments suggest that long-distance migration without jamming is most likely to occur when leading cells specialize in creating ECM fibers, and trailing cells specialize in responding to environmental cues by upregulating mechanisms such as contact guidance.
群体细胞迁移在脊椎动物发育中起着至关重要的作用,但动态变化的微环境对这一现象的影响程度尚不清楚。我们观察到细胞外基质(ECM)成分纤连蛋白在松散连接的神经嵴细胞(NCC)迁移过程中的分布,由此假设 NCC 对初始点状 ECM 的重塑为后续细胞形成了一个支架,使它们能够形成稳健且连贯的流型。我们通过开发一个包含 NCC 与其 ECM 之间相互作用的基于个体的计算模型,在理论环境中评估了这一想法。ECM 重塑、趋化性、接触导向和细胞间排斥足以使细胞在计算机中建立流型,但还需要其他机制(如趋化性)来始终沿正确的目标走廊引导细胞。进一步的模型研究表明,接触导向和先导细胞与跟随细胞之间的差异细胞间排斥是防止流型断裂的关键因素,这有助于稳健的群体细胞迁移。全局敏感性分析和模拟的增益和功能丧失实验表明,当领先细胞专门用于创建 ECM 纤维,而跟随细胞专门通过上调接触导向等机制对环境线索做出反应时,最有可能发生没有堵塞的长距离迁移。