Causality Analysis and Cell Network Modeling of Spatial Calcium Signaling Patterns in Liver Lobules

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.