Institute of Environmental Health, Oregon Health & Science University, Portland, OR, USA.
Division of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University Portland, OR, USA.
Biol Reprod. 2017 Sep 1;97(3):365-377. doi: 10.1093/biolre/iox089.
Despite its importance to reproduction, certain mechanisms of early ovarian development remain a mystery. To improve our understanding, we constructed the first cell-based computational model of ovarian development in mice that is divided into two phases: Phase I spans embryonic day 5.5 (E5.5) to E12.5; and Phase II spans E12.5 to postnatal day 2. We used the model to investigate four mechanisms: in Phase I, (i) whether primordial germ cells (PGCs) undergo mitosis during migration; and (ii) if the mechanism for secretion of KIT ligand from the hindgut resembles inductive cell-cell signaling or is secreted in a static manner; and in Phase II, (iii) that changes in cellular adhesion produce germ cell nest breakdown; and (iv) whether localization of primordial follicles in the cortex of the ovary is due to proliferation of granulosa cells. We found that the combination of the first three hypotheses produced results that aligned with experimental images and PGC abundance data. Results from the fourth hypothesis did not match experimental images, which suggests that more detailed processes are involved in follicle localization. Phase I and Phase II of the model reproduce experimentally observed cell counts and morphology well. A sensitivity analysis identified contact energies, mitotic rates, KIT chemotaxis strength, and diffusion rate in Phase I and oocyte death rate in Phase II as parameters with the greatest impact on model predictions. The results demonstrate that the computational model can be used to understand unknown mechanisms, generate new hypotheses, and serve as an educational tool.
尽管早期卵巢发育的某些机制对生殖至关重要，但仍有许多未解之谜。为了增进我们的理解，我们构建了第一个基于细胞的小鼠卵巢发育计算模型，该模型分为两个阶段：第一阶段跨越胚胎第 5.5 天（E5.5）至 E12.5；第二阶段跨越 E12.5 至出生后第 2 天。我们使用该模型研究了四个机制：在第一阶段，（i）原始生殖细胞（PGC）在迁移过程中是否经历有丝分裂；以及（ii）是否 hindgut 从分泌 KIT 配体的机制类似于诱导细胞间信号传导，或者以静态方式分泌；在第二阶段，（iii）细胞黏附的变化是否导致生殖细胞巢的破裂；以及（iv）原始卵泡在卵巢皮质中的定位是否是由于颗粒细胞的增殖。我们发现，前三个假设的组合产生的结果与实验图像和 PGC 丰度数据一致。第四个假设的结果与实验图像不匹配，这表明卵泡定位涉及更详细的过程。模型的第一阶段和第二阶段很好地再现了实验观察到的细胞计数和形态。敏感性分析确定了第一阶段中的接触能、有丝分裂率、KIT 趋化性强度和扩散率以及第二阶段中的卵母细胞死亡率是对模型预测影响最大的参数。结果表明，该计算模型可用于理解未知机制、生成新假设，并用作教育工具。
