Integrated Causal Network and Model‐based Analysis of Ca2+ Wave Propagation in Liver Lobules

Abstract

Intracellular free Ca2+ in hepatocytes regulates a wide range of hepatic functions. Whole tissue Ca2+ imaging studies show wave‐like spatial patterns of cytosolic Ca2+ in response to circulating hormonal stimuli in liver lobules. Ca2+ waves elicited by hormones such as vasopressin are rooted in cell‐autonomous GPCR activation and the downstream canonical signaling cascade. Spatial Ca2+ waves are caused by gap junction‐mediated molecule exchange between adjacent hepatocytes. Ca2+ waves override cellular heterogeneity with regards to intracellular Ca2+ dynamics leading to a coordinated response to stimuli.Although a wealth of knowledge exists on intracellular Ca2+ dynamics, a quantitative description of lobular scale Ca2+ waves is lacking. We acquired data on vasopressin induced Ca2+ transients imaged in a 2D optical slice in perfused rat liver for 1300 hepatocytes across several lobules. We used a combination of causal time series modeling and model‐based analysis to identify what factors contribute towards propagation of Ca2+ waves in liver lobules.Time series modeling of our data suggested that although Ca2+ waves appeared to traverse entire lobules, only a subset of hepatocytes residing in any lobule formed causally connected “islands”. Within these islands, hepatocytes were causally connected to up to six neighbors. However information flow between adjacent hepatocytes within these islands was not aligned in a unidirectional fashion, as required for wave‐like propagation. Visualization of the Ca2+ profiles within an island revealed existence of cell‐autonomous Ca2+ transients superimposed on spatially propagating waves.We next analyzed our data using a receptor oriented, ODE‐based computational model of Ca2+ wave propagation. Our model suggested that Ca2+ waves originated from extended regions near the pericentral lobular zone and propagated towards the periportal region. Ca2+ waves in our model resulted from parameter gradients and IP3 exchange. Our analysis also revealed that Ca2+ wave propagation was robust to some non‐interacting hepatocytes due to high degree of causal connections for a given hepatocyte.Our analyses revealed that robust lobular scale Ca2+ waves arise due spatial gradients of intracellular signaling components and IP3 exchange between a hepatocyte and several of its neighbors residing within the same island. The existence of multidirectional causal edges as seen in our causal analysis could arise due to cell‐autonomous Ca2+ response of hepatocytes within a small region which do not propagate beyond a few cells. Although we modeled intercellular interactions as gap junction mediated IP3 exchange, additional phenomena such as paracrine signaling as well as cellular arrangement in 3D could contribute towards coupling of hepatocyte Ca2+ responses across sinusoids. These aspects must be included to improve our description of spatial Ca2+ wave dynamics in liver lobules.Support or Funding InformationNIH NIAAA: R01 AA018873This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.