How tissue mechanics control cell differentiationin vivo

生物学的核心问题之一是，受精的卵母细胞在胚胎发育过程中如何能够产生数百种不同类型的细胞，如神经元、肌肉、血细胞等；回答这个问题不仅对生物科学至关重要，而且对细胞治疗具有深远的影响。掌握一种细胞到另一种细胞的转化，称为细胞分化，将使我们能够产生特定的细胞类型，以取代再生治疗中有缺陷的细胞。例如，在神经发生疾病中，有缺陷的神经元需要用健康的神经元取代，这些神经元可以通过细胞分化在体外产生。然而，非神经元细胞是如何分化成A神经元的，目前还知之甚少。很明显，细胞分化受到多种信号的控制，比如化学物质和机械物质。虽然化学信号在控制细胞行为中的作用已被较好地研究，但组织力学如何影响细胞分化仍不清楚，特别是在体内，因为大多数生物力学研究是在体外进行的。在这里，我们将研究组织力学在胚胎发育过程中神经元分化中的作用。我们已经开发出特殊的工具来操纵非洲爪哇胚胎中活组织的力学特性。我们将使用这些工具来修改体内组织的硬度，然后分析神经元的分化。此外，我们还将确定感应机械信号并将其转化为体内神经元分化所需的分子。这一建议的中心目的是阐明胚胎发育过程中细胞力学和命运指定之间相互作用的基本原理。我们希望这种跨学科的方法将为发育生物学中一个核心但尚未解决的问题提供答案：细胞力学和命运规范之间的相互作用如何驱动胚胎发育。

One of the central questions in biology is how a single cell, the fertilized oocyte, is able to generate hundreds of different cell types during embryonic development, like neurons, muscle, blood cells, etc.; answering this questions is not only essential for the biological sciences, but has deep implications in cell therapy. Mastering the transformation of one cell into a different one, called cell differentiation, would allow us to generate specific cell types to replace defective cells during regenerative therapies. For example, in neurogenerative diseases defective neurons need to be replaced by healthy ones that could be generated in vitro by cell differentiation. However, HOW A NON-NEURONAL CELL IS DIFFERENTIATED INTO A NEURON IS POORLY UNDERSTOOD. It is clear that cell differentiation is controlled by diverse cues, such as chemicals and mechanicals. While the role of chemical cues in controlling cell behaviour is comparatively well studied, how tissue mechanics influences cell differentiation remains unknown, especially in vivo, as most of biomechanical studies are performed in vitro. HERE WE WILL STUDY THE ROLE OF TISSUE MECHANICS ON THE DIFFERENTIATION OF NEURONS DURING EMBRYO DEVELOPMENT IN VIVO.We have developed special tools to manipulate the mechanical properties of live tissues in Xenopus embryos. We will use these tools to modify tissue stiffness in vivo followed by analysis of neuronal differentiation. In addition we will identify the molecules required to sense and transduce the mechanical cues into in vivo neuronal differentiation. The central aim of this proposal is to elucidate the fundamental principles underlying the interaction between cell mechanics and fate specification during embryo development. We expect that this transdisciplinary approach will provide answers to a central yet unresolved question in developmental biology: how the interplay between cell mechanics and fate specification drives embryo development.