Ward Daniel, Montes Olivas Sandra, Fletcher Alexander, Homer Martin, Marucci Lucia
Department of Engineering Mathematics, University of Bristol, Bristol BS8 1UB, UK.
School of Mathematics and Statistics, University of Sheffield, Sheffield S3 7RH, UK.
Comput Struct Biotechnol J. 2020 Jan 10;18:230-240. doi: 10.1016/j.csbj.2019.12.015. eCollection 2020.
Intestinal crypts are responsible for the total cell renewal of the lining of the intestines; this turnover is governed by the interplay between signalling pathways and the cell cycle. The role of Wnt signalling in cell proliferation and differentiation in the intestinal crypt has been extensively studied, with increased signalling found towards the lower regions of the crypt. Recent studies have shown that the Wnt signalling gradient found within the crypt may arise as a result of division-based spreading from a Wnt 'reservoir' at the crypt base. The discovery of the Hippo pathway's involvement in maintaining crypt homeostasis is more recent; a mechanistic understanding of Hippo pathway dynamics, and its possible cross-talk with the Wnt pathway, remains lacking. To explore how the interplay between these pathways may control crypt homeostasis, we extended an ordinary differential equation model of the Wnt signalling pathway to include a phenomenological description of Hippo signalling in single cells, and then coupled it to a cell-based description of cell movement, proliferation and contact inhibition in agent-based simulations. Furthermore, we compared an imposed Wnt gradient with a division-based Wnt gradient model. Our results suggest that Hippo signalling affects the Wnt pathway by reducing the presence of free cytoplasmic β-catenin, causing cell cycle arrest. We also show that a division-based spreading of Wnt can form a Wnt gradient, resulting in proliferative dynamics comparable to imposed-gradient models. Finally, a simulated APC double mutant, with misregulated Wnt and Hippo signalling activity, is predicted to cause monoclonal conversion of the crypt.
肠道隐窝负责肠道内衬细胞的全部更新；这种更替受信号通路与细胞周期之间相互作用的调控。Wnt信号在肠道隐窝细胞增殖和分化中的作用已得到广泛研究，发现隐窝下部区域的信号增强。最近的研究表明，隐窝内发现的Wnt信号梯度可能是由于从隐窝底部的Wnt“储存库”基于分裂的扩散所致。Hippo通路参与维持隐窝稳态的发现相对较新；目前仍缺乏对Hippo通路动态及其与Wnt通路可能的相互作用的机制理解。为了探究这些通路之间的相互作用如何控制隐窝稳态，我们扩展了Wnt信号通路的常微分方程模型，以纳入单细胞中Hippo信号的唯象描述，然后将其与基于代理的模拟中基于细胞的细胞运动、增殖和接触抑制描述相结合。此外，我们比较了施加的Wnt梯度与基于分裂的Wnt梯度模型。我们的结果表明，Hippo信号通过减少游离细胞质β-连环蛋白的存在来影响Wnt通路，导致细胞周期停滞。我们还表明，基于分裂的Wnt扩散可以形成Wnt梯度，产生与施加梯度模型相当的增殖动力学。最后，预测具有失调的Wnt和Hippo信号活性的模拟APC双突变体将导致隐窝的单克隆转化。
