Computational Modeling of Spatiotemporal Ca(2+) Signal Propagation Along Hepatocyte Cords.
Computational Modeling of Spatiotemporal Ca(2+) Signal Propagation Along Hepatocyte Cords.
复制标题
沿肝细胞索传播的时空 Ca(2) 信号传播的计算模型。
DOI：
10.1109/tbme.2016.2550045
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Vadigepalli,Rajanikanth
中科院分区：
文献类型：
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作者：
Verma,Aalap;Makadia,Hirenkumar;Hoek,JanB;Ogunnaike,BabatundeA;Vadigepalli,Rajanikanth
本研究的目的是模拟细胞外刺激诱导的小叶钙波传播的动力学，并分析细胞内信号参数的空间系统性变化对正弦钙信号响应的影响。方法我们建立了一个小叶尺度钙信号的计算模型，该模型解释了受体介导的肝细胞内钙信号的启动及其通过缝隙连接介导的分子交换传播到邻近肝细胞。结果模拟分析表明，钙波的传播是由中心到门脉周围的激素敏感性和/或IP3合成速率的空间梯度所致。我们模拟了特定的病例，对应于沿着肝窦的这些参数的分级模式中的局部破坏。结合局部改变的参数的模拟显示，钙波不会传播到整个肝板。当低钙信号传导能力的肝细胞位于小叶中部或中心周围时，间隙连接耦合增强可恢复正常的钙波传播。结论细胞内信号参数的多种空间模式可导致钙波传播，这与实验观察到的钙离子动力学的空间模式一致。基于模拟和分析，我们预测缝隙连接介导的细胞间偶联增加可以在其他反应较差的肝细胞中诱导强烈的钙信号，至少部分恢复正弦方向的钙波。意义我们的激动剂诱发的空间钙离子模式的自下而上模型可以与肝脏组织学的详细描述相结合，在组织水平上研究钙离子调节。
ObjectiveThe purpose of this study is to model the dynamics of lobular Ca2+wave propagation induced by an extracellular stimulus, and to analyze the effect of spatially systematic variations in cell-intrinsic signaling parameters on sinusoidal Ca2+response.MethodsWe developed a computational model of lobular scale Ca2+signaling that accounts for receptor- mediated initiation of cell-intrinsic Ca2+signal in hepatocytes and its propagation to neighboring hepatocytes through gap junction-mediated molecular exchange.ResultsAnalysis of the simulations showed that a pericentral-to-periportal spatial gradient in hormone sensitivity and/or rates of IP3synthesis underlies the Ca2+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 Ca2+waves that do not propagate throughout the hepatic plate. Increased gap junction coupling restored normal Ca2+wave propagation when hepatocytes with low Ca2+signaling ability were localized in the midlobular or the pericentral region.ConclusionMultiple spatial patterns in intracellular signaling parameters can lead to Ca2+wave propagation that is consistent with the experimentally observed spatial patterns of Ca2+dynamics. Based on simulations and analysis, we predict that increased gap junction-mediated intercellular coupling can induce robust Ca2+signals in otherwise poorly responsive hepatocytes, at least partly restoring the sinusoidally oriented Ca2+waves.SignificanceOur bottom-up model of agonist-evoked spatial Ca2+patterns can be integrated with detailed descriptions of liver histology to study Ca2+regulation at the tissue level.