From simple to stratifying epithelia: unifying and diverging adhesive and mechanical principles

从简单到分层上皮：统一和不同的粘合和机械原理

• 批准号: 505673300
• 负责人: Professorin Dr. Carien Niessen, Ph.D.
• 金额: --
• 依托单位: Institut Jacques Monod
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/505673300?language=en
• 关键词: simple; stratifying; epithelia; unifying; diverging

Most tissues are lined by an epithelial barrier that are monolayers as in intestine or multilayered as in the skin. To maintain homeostasis, both types of epithelia renew through a balance between cell division and extrusion. Whereas in simple epithelia cell extrusion results in removal of cells from the monolayer, basal cells of stratified epithelia delaminate while differentiating to generate suprabasal layers.The complex dynamics of epithelia relies on the active nature of their constituent cells giving rise to emergent physical properties, including jamming-unjamming, phase transitions, and active nematics. Whereas our understanding of how physical parameters instruct division and extrusion to make and maintain simple epithelia has advanced greatly in recent years, due to the complex 3D architecture almost nothing is known on the physical properties that shape the formation and maintenance of stratified epithelia.The aim of this project is to understand epithelial stratification by identifying the biomechanical determinants that control cell delamination and suprabasal layer formation and maintenance. We hypothesize that the cellular and supracellular mechanical state of a basal epithelial monolayer determines whether it generates a suprabasal layer and undergo stratification. Using the skin epidermis and primary keratinocytes as paradigms for stratified epithelia we will perform quantitative analysis of the mechanical and molecular parameters of cell delamination, building on our extensive knowledge on these model systems and on cell extrusion from monolayered epithelia, to extract general and tissue specific principles. We will ask which active forces (cytoskeleton contractility, cortical tension) and passive resistive forces (cell-cell and cell-substratum adhesion) are key determinants of stratification versus extrusion and address whether these forces govern the establishment of a boundary between basal and suprabasal layers of the epidermis to make fate compartments. We will integrate experiment and theory to address their global and local impact on traction forces, cell shape and mechanical stress distribution during delamination, 3D cell sorting and boundary formation using in vitro 2D and 3D cellular models. We will consider the role of nematic ordering, cell’s extensile/contractile properties, and of 2D and 3D cell shape disparities to promote local rearrangements, and relate changes in these properties to local and global changes in the adhesive and cytoskeletal repertoire. Finally, we will address the physiological relevance of these in vitro identified principles that cover cell delamination/extrusion for in vivo stratification.Overall, this interdisciplinary project will provide novel insight into the biomechanical principles that enabled epithelia to evolve and switch to stratification to generate a more complex self-renewing barrier.

大多数组织由上皮屏障内衬，如肠中的单层或如皮肤中的多层。为了维持体内平衡，两种类型的上皮细胞通过细胞分裂和挤出之间的平衡来更新。而在简单的上皮细胞挤出导致细胞从单层中去除，复层上皮的基底细胞在分化时分层以产生基底上层。上皮细胞的复杂动力学依赖于其组成细胞的活性性质，从而产生涌现的物理性质，包括堵塞-解除堵塞、相变和活性向列细胞。近年来，我们对物理参数如何指导分裂和挤压以形成和维持简单上皮细胞的理解有了很大的进步，由于复杂的三维结构，几乎没有什么是已知的物理性质，形状的形成和维持分层上皮。本项目的目的是了解上皮分层通过确定生物力学决定因素，控制细胞分层和基底上层形成和维持。我们假设，细胞和超细胞的机械状态的基底上皮单层决定它是否产生一个suprabasal层和分层。使用皮肤表皮和初级角质形成细胞作为分层上皮细胞的范例，我们将进行细胞分层的机械和分子参数的定量分析，建立在我们对这些模型系统和单层上皮细胞挤出的广泛知识基础上，以提取一般和组织特异性原则。我们将问哪些主动力（细胞骨架收缩性，皮质张力）和被动阻力（细胞-细胞和细胞-基质粘附）是分层与挤出的关键决定因素，并解决这些力量是否支配建立表皮基底层和基底上层之间的边界，使命运隔间。我们将整合实验和理论，以解决其全球和局部的影响牵引力，细胞形状和机械应力分布在分层，三维细胞分选和边界形成使用体外2D和3D细胞模型。我们将考虑排序的作用，细胞的伸展/收缩性能，和2D和3D细胞形状的差异，以促进局部重排，并与这些属性的变化，局部和全球的变化，在粘合剂和细胞骨架库。最后，我们将解决这些在体外确定的原则，包括细胞分层/挤出在体内stratify.Overall的生理相关性，这个跨学科的项目将提供新的见解的生物力学原理，使上皮细胞进化和切换到分层，以产生一个更复杂的自我更新的障碍。