Höhme Stefan, Hengstler Jan G, Brulport Marc, Schäfer Marc, Bauer Alexander, Gebhardt Rolf, Drasdo Dirk
Interdisciplinary Centre for Bioinformatics, University of Leipzig, Härtelstr. 16-18, D-04107 Leipzig, Germany.
Chem Biol Interact. 2007 May 20;168(1):74-93. doi: 10.1016/j.cbi.2007.01.010. Epub 2007 Feb 2.
Liver regeneration is a complex process, having evolved to protect animals from the consequences of liver loss caused by food toxins. In this study, we established a mathematical spatial-temporal model of the liver lobule regenerating after CCl(4) intoxication. The aim of modelling the regeneration process by matching experimental observations with those from a mathematical model is to gain a better understanding of the process and to recognize which parameters are relevant for specific phenomena. In order to set up a realistic minimal model, we first reconstructed a schematised liver lobule after determination of: (i) the mean number of hepatocytes between the central vein and the periphery of the lobule, (ii) the mean size of the hepatocytes and (iii) the mean number of hepatocyte columns in the inner, midzonal and peripheral ring of the lobule. In a next step, we determined the time course of cell death and BrdU incorporation after intoxication of male Sprague Dawley rats with CCl(4), thereby differentiating between inner, midzonal and peripheral hepatocytes. These parameters were used to construct a model. The basic unit of this model is the individual cell. The detailed behaviour of the cells is studied, controlled by the model parameters: (1) probability of cell division at defined positions of the lobule at a given time, (2) "coordinated cell orientation", i.e., the ability of the cells to align during the regeneration process into columns towards the central vein of a liver lobule, (3) cell cycle duration, (4) the migration activity and (5) the polarity of the hepatocytes resulting in polar cell-cell adhesion between them. In a schematised lobule, the model shows that CCl(4) initially induced cell death of a pericentral ring of hepatocytes, followed by a wave of proliferation that starts in the surviving hepatocytes next to the inner ring of dead cells and continues to the peripheral hepatocytes, finally restoring the characteristic micro-architecture of the lobule in a 7-day process. This model was used to systematically analyze the influence of parameters 1-5. Interestingly, coordinated cell orientation and cell polarity were identified to be the most critical parameters. Elimination led to destruction of the characteristic micro-architecture of the lobule and to a high degree of disorder characterized by hexagonal cell structures. Our model suggests that the ability of hepatocytes to realign after cell division by a process of coordinated cell orientation (model parameter 2) in combination with cell polarity (model parameter 5) may be at least as critical as hepatocyte proliferation (model parameter 1) itself.
肝脏再生是一个复杂的过程，其进化是为了保护动物免受食物毒素导致的肝脏损失的后果。在本研究中，我们建立了四氯化碳中毒后肝小叶再生的数学时空模型。通过将实验观察结果与数学模型的结果相匹配来对再生过程进行建模的目的是更好地理解该过程，并识别哪些参数与特定现象相关。为了建立一个现实的最小模型，我们首先在确定以下内容后重建了一个示意性的肝小叶：（i）中央静脉与小叶周边之间肝细胞的平均数量，（ii）肝细胞的平均大小，以及（iii）小叶内圈、中区和外周环中肝细胞柱的平均数量。在下一步中，我们确定了雄性Sprague Dawley大鼠用四氯化碳中毒后细胞死亡和溴脱氧尿苷掺入的时间进程，从而区分内圈、中区和外周肝细胞。这些参数被用于构建一个模型。该模型的基本单元是单个细胞。研究了细胞的详细行为，由模型参数控制：（1）在给定时间小叶特定位置的细胞分裂概率，（2）“协调细胞定向”，即细胞在再生过程中朝着肝小叶中央静脉排列成柱的能力，（3）细胞周期持续时间，（4）迁移活性，以及（5）肝细胞的极性导致它们之间的极性细胞 - 细胞粘附。在一个示意性的小叶中，该模型表明四氯化碳最初诱导中央周围肝细胞环的细胞死亡，随后是一波增殖，从死亡细胞内圈旁边存活的肝细胞开始，并持续到外周肝细胞，最终在7天的过程中恢复小叶的特征性微结构。该模型被用于系统分析参数1 - 5的影响。有趣的是，协调细胞定向和细胞极性被确定为最关键的参数。消除这些参数会导致小叶特征性微结构的破坏，并导致以六边形细胞结构为特征的高度紊乱。我们的模型表明，肝细胞在细胞分裂后通过协调细胞定向过程（模型参数2）与细胞极性（模型参数5）重新排列的能力可能至少与肝细胞增殖（模型参数1）本身一样关键。
