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Physical mechanisms driving mesendoderm collective cell migration

驱动中内胚层集体细胞迁移的物理机制

基本信息

批准号：
BB/T016493/1
负责人：
Michael Smutny
金额：
$ 64.71万
依托单位：
University of Warwick
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FT016493%2F1
关键词：
Physical mechanisms driving mesendoderm collective

项目摘要

One of the main features of life is movement, either as a single entity or in groups. Collective cell migration is characterizedas the behaviour of a group of cells which moves together more efficiently than its components in isolation. It is a fundamental process seen in all multicellular animals and is essential for physiological functions such as wound healing and immune cell surveillance in adults. During embryonic development, collective cell migration is a hallmark of cellular rearrangements and ensures accurate formation of organs and tissues. Invading and metastatic cancer cells can also migrate as collectives thus making this process highly relevant during cancer metastasis.The mechanisms guiding collectively migrating cells vary and can depend on inherent cellular reorganisation events such as establishment of leader and follower (trailing) cells and on external signals from the microenvironment which act as guidance cues ("inputs"), ultimately generating a collective response for directional migration. The cells in the collective respond to and communicate with each other through biochemical and physical interactions enabled by cell-cell connections (adhesions), thereby coordinating efficient movement. Guidance as well as the intercellular communication can be mediated through physical/mechanical, chemical and/or electrical cues. Extensive studies have revealed the role of major signalling molecules (chemokines) in collective migration. However, recent findings emphasise that mechanical stimuli (pulling, pushing, shear) and physical properties of the surrounding may be equally important for cell migration. Yet, our knowledge of how these physical factors contribute to collective cell migration within living organisms and the underlying mechanisms remain very limited.The zebrafish embryo constitutes an ideal model organism to study cell migration, as the embryos are transparent and perfectly suited for live cell imaging. Furthermore, it is a highly accessible system where specific cells can be transferred between different embryos (transplantations) or isolated from the embryo for ex vivo experiments. We will focus our research on the mesendoderm tissue, which is a cell collective that is highly conserved in vertebrates and is fundamental for early embryonic development. Mesendoderm cells migrate as a collective along the future head-tail body axis of the embryo and failure in precise collective migration results in embryonic defects in eye and brain and body axis malformations leading to organ degeneration or early embryonic death.To address the physical basis of mesendoderm collective migration, we will use a highly interdisciplinary approach combining methods and tools from biology, physics and theoretical modelling. We will identify mechanical cues and physical properties of the microenvironment that influence collective migration, and investigate how these signals are transduced through the collective. We will further study how physical barriers and adhesive surfaces contribute to cell migration. Finally, a mathematical model will be developed that aims to recapitulate polarization and directional movements of a collective based on the minimal essential physical parameters.In summary, the outcomes of the proposed research will have significant impact on our understanding of physical mechanisms that drive collective cell migration of mesendoderm cells in the embryo. This will be essential in expanding our knowledge of embryonic development and will also serve as a framework to understand behaviours of other collectively moving systems in physiological and pathological contexts.

生命的主要特征之一是运动，无论是作为单个实体还是群体。集体细胞迁移的特征是一组细胞的行为，它们一起移动比单独移动更有效。这是所有多细胞动物中的一个基本过程，对于成年人的伤口愈合和免疫细胞监视等生理功能至关重要。在胚胎发育期间，集体细胞迁移是细胞重排的标志，并确保器官和组织的准确形成。侵入和转移的癌细胞也可以集体迁移，从而使这一过程在癌症转移期间高度相关。引导集体迁移细胞的机制各不相同，并且可以取决于固有的细胞重组事件，例如建立领导者和跟随者（尾随）细胞，以及来自微环境的外部信号，其作为指导线索（“输入”），最终产生定向迁移的集体反应。集体中的细胞通过细胞-细胞连接（粘附）实现的生物化学和物理相互作用相互响应和交流，从而协调有效的运动。指导以及细胞间通讯可以通过物理/机械，化学和/或电线索介导。广泛的研究揭示了主要信号分子（趋化因子）在集体迁移中的作用。然而，最近的研究结果强调，机械刺激（拉，推，剪）和周围的物理特性可能是同样重要的细胞迁移。然而，我们对这些物理因素如何促进活生物体内的集体细胞迁移及其潜在机制的了解仍然非常有限。斑马鱼胚胎是研究细胞迁移的理想模型生物，因为胚胎是透明的，非常适合活细胞成像。此外，它是一个高度可及的系统，其中特定的细胞可以在不同的胚胎之间转移（移植）或从胚胎中分离用于离体实验。我们将把研究重点放在中内胚层组织上，这是一种在脊椎动物中高度保守的细胞集合，是早期胚胎发育的基础。中内胚层细胞作为一个集体沿着未来的头-尾体轴的胚胎和精确的集体迁移失败的结果在胚胎缺陷的眼睛和大脑和体轴畸形导致器官退化或早期胚胎死亡。为了解决中内胚层集体迁移的物理基础，我们将使用一个高度跨学科的方法，结合从生物学，物理学和理论建模的方法和工具。我们将识别影响集体迁移的微环境的机械线索和物理特性，并研究这些信号是如何通过集体转导的。我们将进一步研究物理屏障和粘附表面如何促进细胞迁移。最后，将开发一个数学模型，旨在概括基于最小基本物理参数的集体极化和定向运动。总之，拟议研究的结果将对我们理解驱动胚胎中内胚层细胞集体迁移的物理机制产生重大影响。这将是至关重要的，在扩大我们的知识胚胎发育，也将作为一个框架，以了解其他集体运动系统在生理和病理背景下的行为。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Translational control of furina by an RNA regulon is essential for heart morphogenesis and cardiac valve function

DOI：
10.1101/2023.01.30.526270
发表时间：
2023-02
期刊：
bioRxiv
影响因子：
0
作者：
Agnieszka Nagorska;Finnlay R. P. Lambert;Angus Inman;Sara Toral-Perez;A. Zaucker;J. Gorodkin;Wan Yue;Michael Smutny;K. Sampath
通讯作者：
Agnieszka Nagorska;Finnlay R. P. Lambert;Angus Inman;Sara Toral-Perez;A. Zaucker;J. Gorodkin;Wan Yue;Michael Smutny;K. Sampath

Emerging Role of Mechanical Forces in Cell Fate Acquisition.