Verma Aalap, Makadia Hirenkumar, Hoek Jan B, Ogunnaike Babatunde A, Vadigepalli Rajanikanth
IEEE Trans Biomed Eng. 2016 Oct;63(10):2047-55. doi: 10.1109/TBME.2016.2550045. Epub 2016 Apr 4.
The purpose of this study is to model the dynamics of lobular Ca(2+) wave propagation induced by an extracellular stimulus, and to analyze the effect of spatially systematic variations in cell-intrinsic signaling parameters on sinusoidal Ca(2+) response.
We developed a computational model of lobular scale Ca(2+) signaling that accounts for receptor- mediated initiation of cell-intrinsic Ca(2+) signal in hepatocytes and its propagation to neighboring hepatocytes through gap junction-mediated molecular exchange.
Analysis of the simulations showed that a pericentral-to-periportal spatial gradient in hormone sensitivity and/or rates of IP3 synthesis underlies the Ca(2+) wave propagation. We simulated specific cases corresponding to localized disruptions in the graded pattern of these parameters along a hepatic sinusoid. Simulations incorporating locally altered parameters exhibited Ca(2+) waves that do not propagate throughout the hepatic plate. Increased gap junction coupling restored normal Ca(2+) wave propagation when hepatocytes with low Ca(2+) signaling ability were localized in the midlobular or the pericentral region.
Multiple spatial patterns in intracellular signaling parameters can lead to Ca(2+) wave propagation that is consistent with the experimentally observed spatial patterns of Ca(2+) dynamics. Based on simulations and analysis, we predict that increased gap junction-mediated intercellular coupling can induce robust Ca(2+) signals in otherwise poorly responsive hepatocytes, at least partly restoring the sinusoidally oriented Ca (2+) waves.
Our bottom-up model of agonist-evoked spatial Ca(2+) patterns can be integrated with detailed descriptions of liver histology to study Ca(2+) regulation at the tissue level.
本研究旨在模拟细胞外刺激诱导的小叶钙（Ca(2+)）波传播动力学，并分析细胞内信号参数的空间系统性变化对正弦Ca(2+)反应的影响。
我们开发了一种小叶尺度Ca(2+)信号的计算模型，该模型考虑了受体介导的肝细胞内源性Ca(2+)信号的启动及其通过间隙连接介导的分子交换向邻近肝细胞的传播。
模拟分析表明，激素敏感性和/或IP3合成速率从中央到周边的空间梯度是Ca(2+)波传播的基础。我们模拟了与沿肝血窦这些参数的梯度模式局部破坏相对应的特定情况。纳入局部改变参数的模拟显示，Ca(2+)波不会在整个肝板中传播。当低Ca(2+)信号传导能力的肝细胞位于小叶中部或中央区域时，增加间隙连接耦合可恢复正常的Ca(2+)波传播。
细胞内信号参数的多种空间模式可导致Ca(2+)波传播，这与实验观察到的Ca(2+)动力学空间模式一致。基于模拟和分析，我们预测增加间隙连接介导的细胞间耦合可在原本反应不佳的肝细胞中诱导强大的Ca(2+)信号，至少部分恢复沿血窦方向的Ca(2+)波。
我们的激动剂诱发的空间Ca(2+)模式的自下而上模型可与肝脏组织学的详细描述相结合，以研究组织水平的Ca(2+)调节。
