细胞增殖的调节是组织发育和体内平衡的一个重要方面,在形态发生中起着重要作用。伤口愈合,和肿瘤侵袭。这种调节的现象是接触抑制,描述了扩散的急剧放缓,当多个细胞彼此接触时,细胞迁移和单个细胞生长。虽然许多生理,分子和遗传因素是已知的,接触抑制的机理尚不完全清楚。特别是,由于界面接触引起的细胞信号传导与接触抑制的相关性仍存在争议。过去,细胞自动机(CA)已被用作数值有效的数学模型来研究细胞集合的动力学,但是它们不适合探索接触抑制的起源,因为这种基于试剂的模型假设细胞大小固定。我们开发了一个最小的,数据驱动模型通过扩展概率CA来模拟平面细胞培养物的动力学,以纳入生长和细胞分裂过程中单个细胞的大小变化。我们成功地将此模型应用于先前关于上皮组织接触抑制的体外实验:在系统校准模型参数以测量单细胞动力学之后,我们的CA模型定量地再现了对突发事件的独立测量,文化广泛的特点,像菌落大小一样,细胞密度和集体细胞迁移。特别是,CA模型的动力学还表现出从低密度汇合状态到静止的汇合后状态的过渡,细胞大小和运动迅速减小。这意味着体积排除原则,机械约束是模型中唯一包含的细胞间相互作用,与大小依赖性增殖率配对足以产生观察到的接触抑制。我们讨论了我们的方法如何在CA框架中引入有效的生物机械相互作用,以供未来研究使用。
Regulation of cell proliferation is a crucial aspect of tissue development and homeostasis and plays a major role in morphogenesis, wound healing, and tumor invasion. A phenomenon of such regulation is contact inhibition, which describes the dramatic slowing of proliferation, cell migration and individual cell growth when multiple cells are in contact with each other. While many physiological, molecular and genetic factors are known, the mechanism of contact inhibition is still not fully understood. In particular, the relevance of cellular signaling due to interfacial contact for contact inhibition is still debated. Cellular automata (CA) have been employed in the past as numerically efficient mathematical models to study the dynamics of cell ensembles, but they are not suitable to explore the origins of contact inhibition as such agent-based models assume fixed cell sizes. We develop a minimal, data-driven model to simulate the dynamics of planar cell cultures by extending a probabilistic CA to incorporate size changes of individual cells during growth and cell division. We successfully apply this model to previous in-vitro experiments on contact inhibition in epithelial tissue: After a systematic calibration of the model parameters to measurements of single-cell dynamics, our CA model quantitatively reproduces independent measurements of emergent, culture-wide features, like colony size, cell density and collective cell migration. In particular, the dynamics of the CA model also exhibit the transition from a low-density confluent regime to a stationary postconfluent regime with a rapid decrease in cell size and motion. This implies that the volume exclusion principle, a mechanical constraint which is the only inter-cellular interaction incorporated in the model, paired with a size-dependent proliferation rate is sufficient to generate the observed contact inhibition. We discuss how our approach enables the introduction of effective bio-mechanical interactions in a CA framework for future studies.