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Integrated Causal Network and Model‐based Analysis of Ca 2+ Wave Propagation in Liver Lobules
Author(s) -
Verma Aalap,
Antony Anil,
Makadia Hiren,
Ogunnaike Babatunde,
Hoek Jan,
Vadigepalli Rajanikanth
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.863.5
Subject(s) - intracellular , sinusoid , gap junction , vasopressin , biology , biophysics , microbiology and biotechnology , chemistry , physics , endocrinology , immunology
Intracellular free Ca 2+ in hepatocytes regulates a wide range of hepatic functions. Whole tissue Ca 2+ imaging studies show wave‐like spatial patterns of cytosolic Ca 2+ in response to circulating hormonal stimuli in liver lobules. Ca 2+ waves elicited by hormones such as vasopressin are rooted in cell‐autonomous GPCR activation and the downstream canonical signaling cascade. Spatial Ca 2+ waves are caused by gap junction‐mediated molecule exchange between adjacent hepatocytes. Ca 2+ waves override cellular heterogeneity with regards to intracellular Ca 2+ dynamics leading to a coordinated response to stimuli. Although a wealth of knowledge exists on intracellular Ca 2+ dynamics, a quantitative description of lobular scale Ca 2+ waves is lacking. We acquired data on vasopressin induced Ca 2+ 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 Ca 2+ waves in liver lobules. Time series modeling of our data suggested that although Ca 2+ 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 Ca 2+ profiles within an island revealed existence of cell‐autonomous Ca 2+ transients superimposed on spatially propagating waves. We next analyzed our data using a receptor oriented, ODE‐based computational model of Ca 2+ wave propagation. Our model suggested that Ca 2+ waves originated from extended regions near the pericentral lobular zone and propagated towards the periportal region. Ca 2+ waves in our model resulted from parameter gradients and IP 3 exchange. Our analysis also revealed that Ca 2+ 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 Ca 2+ waves arise due spatial gradients of intracellular signaling components and IP 3 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 Ca 2+ response of hepatocytes within a small region which do not propagate beyond a few cells. Although we modeled intercellular interactions as gap junction mediated IP 3 exchange, additional phenomena such as paracrine signaling as well as cellular arrangement in 3D could contribute towards coupling of hepatocyte Ca 2+ responses across sinusoids. These aspects must be included to improve our description of spatial Ca 2+ wave dynamics in liver lobules. Support or Funding Information NIH NIAAA: R01 AA018873 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .