Verma Aalap, Antony Anil Noronha, Ogunnaike Babatunde A, Hoek Jan B, Vadigepalli Rajanikanth
Department of Biomedical Engineering, University of Delaware, Newark, DE, United States.
Department of Pathology, Anatomy and Cell Biology, Daniel Baugh Institute for Functional Genomics and Computational Biology, Thomas Jefferson University, Philadelphia, PA, United States.
Front Physiol. 2018 Oct 4;9:1377. doi: 10.3389/fphys.2018.01377. eCollection 2018.
Dynamics as well as localization of Ca transients plays a vital role in liver function under homeostatic conditions, repair, and disease. In response to circulating hormonal stimuli, hepatocytes exhibit intracellular Ca responses that propagate through liver lobules in a wave-like fashion. Although intracellular processes that control cell autonomous Ca spiking behavior have been studied extensively, the intra- and inter-cellular signaling factors that regulate lobular scale spatial patterns and wave-like propagation of Ca remain to be determined. To address this need, we acquired images of cytosolic Ca transients in 1300 hepatocytes situated across several mouse liver lobules over a period of 1600 s. We analyzed this time series data using correlation network analysis, causal network analysis, and computational modeling, to characterize the spatial distribution of heterogeneity in intracellular Ca signaling components as well as intercellular interactions that control lobular scale Ca waves. Our causal network analysis revealed that hepatocytes are causally linked to multiple other co-localized hepatocytes, but these influences are not necessarily aligned uni-directionally along the sinusoids. Our computational model-based analysis showed that spatial gradients of intracellular Ca signaling components as well as intercellular molecular exchange are required for lobular scale propagation of Ca waves. Additionally, our analysis suggested that causal influences of hepatocytes on Ca responses of multiple neighbors lead to robustness of Ca wave propagation through liver lobules.
在稳态条件、修复及疾病状态下，钙瞬变的动力学及定位在肝功能中起着至关重要的作用。响应循环激素刺激，肝细胞表现出细胞内钙反应，该反应以波状方式在肝小叶中传播。尽管已经广泛研究了控制细胞自主钙尖峰行为的细胞内过程，但调节小叶尺度空间模式和钙波状传播的细胞内和细胞间信号因子仍有待确定。为满足这一需求，我们在1600秒的时间内获取了横跨多个小鼠肝小叶的1300个肝细胞中胞质钙瞬变的图像。我们使用相关网络分析、因果网络分析和计算建模对该时间序列数据进行分析，以表征细胞内钙信号成分异质性的空间分布以及控制小叶尺度钙波的细胞间相互作用。我们的因果网络分析表明，肝细胞与多个其他共定位的肝细胞存在因果联系，但这些影响不一定沿肝血窦单向排列。我们基于计算模型的分析表明，细胞内钙信号成分的空间梯度以及细胞间分子交换是钙波在小叶尺度传播所必需的。此外，我们的分析表明，肝细胞对多个相邻细胞钙反应的因果影响导致钙波通过肝小叶传播的稳健性。
