Regulation of cell division by mechanical force in tissues: speed versus strength

我们身体的细胞和组织不断地被推动和拉动，它们必须适当地感知和响应这些机械力，以维持正常的组织功能。虽然我们开始了解一些将细胞行为与孤立细胞中的机械力联系起来的细胞机制，但我们对这一机制如何应用于我们身体的复杂组织知之甚少。考虑到组织在胚胎中形成和塑造以及随着组织老化和成年后患病(例如通过癌症)而发生的重大机械变化，弥合这一差距是重要的。在这个项目中，我们将研究复杂胚胎组织中的基本细胞功能-细胞分裂-是如何受机械力调节的。在最近的工作中，我们已经表明，上皮细胞对低水平的拉伸(拉伸)力非常敏感，这会增加它们的细胞分裂率，并沿着拉伸轴重定向分裂2。对于这个博士项目，我们将在这些发现的基础上提出一个关键的问题：拉伸的速度如何改变细胞分裂的调节？这一点很重要，因为到目前为止所有的研究都集中在细胞的快速伸展上，而不是反映胚胎和成人组织中最常见的较慢的伸展。在初步数据中，我们发现组织对慢速伸展和快速伸展的反应方式存在显著差异。这些结果有可能改变我们对细胞和组织的机械调节的看法。对于他们的博士学位，学生将：1.使用实时共聚焦显微镜来成像拉伸和未拉伸组织中的细胞分裂。开发/应用数学模型来理解组织中机械力的模式3，4.3。确定肌动蛋白细胞骨架和膜张力的调节如何控制组织对力的反应。这是一个跨学科的项目，非常适合来自广泛学术学科的学生：生物、数学和物理。该项目的确切内容可以根据选定候选人的学术背景进行调整，并将为细胞和发育生物学及其与生物物理学和数学的交叉提供坚实的基础。学生将建立多样化和新颖的技能组合，结合胚胎学、高级显微镜和尖端数学/计算分析，并将受益于科学家团队的监督，他们带来了互补的专业领域和多年监督此类跨学科项目的经验。

The cells and tissues of our bodies are constantly being pushed and pulled and it is vital that they sense and respond to these mechanical forces appropriately to maintain normal tissue function1. Whilst we are beginning to understand some of the cellular mechanisms that link cell behaviour with mechanical force in isolated cells, we know much less about how this applies to the complex tissues of our bodies. Bridging this gap is important considering the significant mechanical changes that take place in tissues as they are formed and shaped in the embryo and as they age and become diseased (e.g. via cancer) in the adult.In this project, we will investigate how a fundamental cellular function - cell division - is regulated by mechanical force in a complex embryonic tissue. In recent work, we have shown that epithelial cells are exquisitely sensitive to low levels of stretching (tensile) force, which increases their cell division rate and reorients divisions along the axis of stretch2. For this PhD project, we will build on these findings to ask a crucial question: how does the speed of a stretch alter the regulation of cell division? This is important because all studies to date have focused on fast stretches of cells, which don't reflect the slower stretches that most commonly occur in embryonic and adult tissue. In preliminary data we find marked differences in how a tissue responds to slow versus fast stretches. These results have the potential to change how we think about mechanical regulation of cells and tissues.For their PhD, the student will:1. Use live confocal microscopy to image cell division in stretched and unstretched tissue.2. Develop/apply mathematical modelling to understand patterns of mechanical force in tissue3,4.3. Determine how the regulation of the actin cytoskeleton and membrane tension5 control tissue responses to force.This is an interdisciplinary project that is well-suited to students from a wide range of academic disciplines: biological, mathematical and physical. The exact content of the project can be adapted according to the academic background of the selected candidate and will provide a solid foundation in cell and developmental biology and its intersection with biophysics and mathematics. The student will build a diverse and novel skill set, combining embryology, advanced microscopy and cutting-edge mathematical/computational analysis and will benefit from supervision by a team of scientists who bring complementary areas of expertise and years of experience supervising interdisciplinary projects of this kind.