Deciphering the role of mechanics for epithelia trans-differentiation

解读上皮转分化的力学作用

• 批准号: 414058537
• 负责人: Dr. Alba Diz-Muñoz
• 金额: --
• 依托单位: Europäisches Laboratorium für Molekularbiologie (EMBL)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/414058537?language=en
• 关键词: Deciphering; role; mechanics; epithelia; trans

In the last decade it has become clear that cellular and microenvironment mechanics affect epithelia integrity and cell fate. Upon mechanical injury of the zebrafish notochord, cell fate plasticity occurs as epithelial sheath cells trans-differentiatiate into non-epithelial vacuolated ones. For sheath tissue integrity, such trans-differentiation requires the coordination of the cell’s cytoskeleton with a concomitant rearrangement of their cell-cell junctions. A clear understanding of the molecular and physical mechanisms governing cell trans-differentiation in vivo have been hampered by the lack of convenient assay systems and tools to assess and perturb mechanical properties in 3D environments. In this proposal, we will first characterize cell-cell junctions in sheath cells by light and electron microscopy, while quantifying tissue stiffness by Brillouin microscopy upon controlled vacuolated cell death (Objective 1). Next, we will perturb the balance of forces between neighbouring sheath cells by developing strategies to systematically change tissue stiffness, neighbouring cell contractility and adhesion, while assessing their effect on fate and cell-cell junctions’ dynamics during epithelia trans-differentiation (Objective 2).

在过去的十年中，细胞和微环境机制影响上皮细胞的完整性和细胞的命运已经变得很清楚。斑马鱼脊索受到机械损伤后，随着上皮鞘细胞反式分化为非上皮空泡化细胞，细胞命运可塑性发生。对于鞘组织的完整性，这种反式分化需要细胞的细胞骨架的协调，以及伴随而来的细胞-细胞连接的重新排列。由于缺乏方便的检测系统和工具来评估和扰乱3D环境中的机械性能，对体内细胞转分化的分子和物理机制的清楚理解一直受到阻碍。在这项建议中，我们将首先通过光学和电子显微镜表征鞘细胞中的细胞-细胞连接，同时通过受控空泡化细胞死亡的布里渊显微镜来量化组织硬度(目标1)。接下来，我们将通过制定系统地改变组织硬度、相邻细胞收缩和黏附的策略来扰乱相邻鞘细胞之间的力的平衡，同时评估它们在上皮转分化过程中对命运和细胞-细胞连接动力学的影响(目标2)。