(568b) Simulating Ca2+ Signal Propagation in Exact 3D Reconstructions of Hepatic Lobules
We performed an integrated in vivo imaging, data-driven causality analysis, and computational model-based analysis of Ca2+ signal propagation in mouse liver lobules. Simulations of ODE-based models in one- and two-dimensional representations of liver tissue suggested that lobular scale Ca2+ waves require spatially organized gradients in the expression of hormonal signaling components as well as IP3 exchange between adjacent hepatocytes1,2. Based on the experimentally observed wave-like propagation, we hypothesized that the cell-cell causal influences unidirectionally radiate outward in a sequential manner from pericentral vein to periportal vein in a liver lobule. However, a data-driven, causal network modeling of potential pair-wise influences between 1300 individual hepatocytes suggested that spatially co-localized subsets of cells formed causally connected âislandsâ. Within these islands, hepatocytes were causally connected to up to six neighbors. The predicted information flow between adjacent hepatocytes within these islands was not consistently aligned in a unidirectional fashion from central vein towards portal triads.
We extended the ODE-based modeling to incorporate three-dimensional topology and cell-cell contacts in hepatic lobules, and examined the dynamics of Ca2+ wave propagation in a three-dimensionally organized liver tissue. We acquired high resolution confocal images of sections of hepatic lobules up to 100 Î¼m in thickness. We segmented hepatocytes, and hepatic vasculature in the acquired z-stack of images to generate an exact reconstruction of the imaged tissue volume. We then simulated an ODE-based computational model of intra- and inter-cellular signaling using the reconstructed 3D tissue architecture to investigate the contribution of lobular topology to Ca2+ signal propagation. In the simulations, the expression of two hormonal signaling components, represented by two cell-specific model parameters, were initialized based on published single cell transcriptomic data3.
Our simulations revealed that with model initialization based on single cell transcriptomic data in , flow of Ca2+ signal from the central vein towards the portal triads requires gap junction mediated IP3 exchange between adjacent hepatocytes. Additionally, information flow between adjacent hepatocytes within a 2D slice may not be aligned in a unidirectional fashion, as observed in our data-driven causality analysis in , likely because of cell-cell contacts in 3D lobular topology.
- Verma, Aalap, Hirenkumar Makadia, Jan B. Hoek, Babatunde A. Ogunnaike, and Rajanikanth Vadigepalli. "Computational Modeling of Spatiotemporal Ca2+ Signal Propagation Along Hepatocyte Cords." IEEE Transactions on Biomedical Engineering 63, no. 10 (2016): 2047-2055.
- Verma, Aalap, Anil Noronha Antony, Babatunde A. Ogunnaike, Jan B. Hoek and Rajanikanth Vadigepalli. âCausality Analysis and Cell Network Modeling of Spatial Calcium Signaling Patterns in Liver Lobules.â Frontiers in Physiology, under review
- Halpern, Keren Bahar, Rom Shenhav, Orit Matcovitch-Natan, BeÃ¡ta TÃ³th, Doron Lemze, Matan Golan, Efi E. Massasa et al. "Single-cell spatial reconstruction reveals global division of labour in the mammalian liver." Nature 542, no. 7641 (2017): 352.