Mathematical modelling of tissue development

生物学中的一个基本问题是单个真核细胞（例如，受精卵，干细胞）产生发育成完整的多细胞生物体所需的复杂性。这种单细胞分裂并启动精心策划的事件，引导后代及时分化和多样化，以产生由数十亿个细胞组成的功能组织。组织发育涉及许多调节机制，但它们如何协调并以受控方式进行这一复杂过程仍有待发现。组织发育中涉及的一个关键时间机制是细胞周期。细胞周期持续时间影响细胞生长和分裂的时间。在早期组织发育中，细胞周期持续时间发生显著变化，开始快速生成细胞，并随着细胞分化而减慢。这些变化的细胞周期持续时间可以通过控制长基因转录物的表达在组织发育中发挥重要作用，长基因转录物在短细胞周期中部分转录。基因必须完全转录才能表达。利用细胞增殖的数学模拟，我们最近发现了一个新的特性，即这种“转录过滤器”可以作为一个调节旋钮来控制细胞多样性的产生，以及组织中不同细胞类型的数量和比例。我们的预测得到了与胚胎发育过程中捕获的单细胞RNA-seq数据以及进化基因组分析的比较的支持。我们的研究结果支持细胞周期动力学对控制基因转录表达和组织内多样性很重要的观点。在这里，我们将扩展这项工作，并探讨不同的调节机制如何影响多细胞动物的细胞命运和正常组织发育。我们将通过建立一个组织发育的数学模型来解决这个问题，该模型捕捉了细胞机制如何影响细胞命运的决定和时间以及空间模式。我们将根据两个长期目标开展这项工作。首先，我们将研究细胞分化和产生组织发育所需的各种细胞类型时的过渡时间。我们将探索一系列可能影响组织发育时间的机制，如细胞周期动力学，细胞间通讯和基因调控网络。其次，我们将探讨我们模型的机制如何影响空间组织的自组织和发展。我们将扩展我们现有的数学模型，以包括2D和3D几何形状，并探索细胞如何在这些空间内分化和自组织。我们对细胞命运控制和组织发育的数学探索有望产生广泛的影响，因为我们研究的细胞周期和其他调控机制动态在发育中，随着细胞老化，再生和修复以及肿瘤生长过程中非常重要。我们的工作有可能从根本上改变我们对这些过程的看法。

A fundamental question in biology is how a single eukaryotic cell (e.g., zygote, stem cell) produces the complexity required to develop into a complete multicellular organism. This single cell divides and initiates the orchestrated events guiding progeny to differentiate and diversify in a timely manner to generate functional tissue composed of billions of cells. Tissue development involves many regulatory mechanisms, but it remains to be discovered how they coordinate and carry out this complex process in a controlled fashion. One key temporal mechanism involved in tissue development is the cell cycle. Cell cycle duration influences the amount of time a cell has to grow and divide. In early tissue development, cell cycle duration changes dramatically, starting out fast to generate cells quickly and slowing down as cells differentiate. These changing cell cycle durations can play an important role in tissue development by controlling the expression of long gene transcripts, which are partially transcribed in short cell cycles. Genes must be fully transcribed to be expressed. Using mathematical simulations of cell proliferation, we recently identified an emergent property that this "transcriptional filter" can act as a tuning knob to control the generation of cell diversity, and the number and proportion of different cell types in a tissue. Our predictions are supported by comparison to single-cell RNA-seq data captured over embryonic development, as well as evolutionary genome analysis. Our results support the idea that cell cycle dynamics are important for controlling gene transcript expression and the diversity within a tissue. Here, we will extend this work and explore how diverse regulatory mechanisms can affect cell fate and normal tissue development in multicellular animals. We will address this by building a mathematical model of tissue development that captures how cellular mechanisms affect cell fate decisions and timing as well as spatial patterning. We will undertake this work following two long-term objectives. First, we will study the timing of transitions as cells differentiate and generate the various cell types needed for tissue development. We will explore a range of mechanisms, such as cell cycle dynamics, cell-cell communication and gene regulatory networks, that may affect tissue development timing. Second, we will explore how the mechanisms we model impact spatial tissue self-organization and development. We will extend our existing mathematical model to include 2D and 3D geometry and explore how cells differentiate and self-organize within these spaces. Our mathematical exploration of cell fate control and tissue development promises to have broad impact, as cell cycle and other regulatory mechanism dynamics we study are important in development, as cells age, during regeneration and repair, and during tumour growth. Our work has the potential to fundamentally alter the way we think about these processes.