The auxetic nucleus: nuclear mechanotransduction and its role in regulating stem cell differentiation

拉胀核：核力转导及其在调节干细胞分化中的作用

• 批准号: BB/M008827/1
• 负责人: Kevin Chalut
• 金额: $ 76.86万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM008827%2F1
• 关键词: auxetic; nucleus; nuclear; mechanotransduction; its

Embryonic stem cells (ESCs) self-renew in a state of pluripotency, meaning they can give rise to all tissue types; therefore, they are very promising for regenerative medicine. We recently discovered they have a very interesting and surprising property. Just as an ESC begins to leave behind this state of pluripotency - i.e. as it differentiates - their nucleus, the large structure in the cell that houses all the genetic material, becomes 'auxetic'. Auxeticity is a property that refers to the response of a material under mechanical stress. Consider that, under mechanical stress, a tensed rubber band becomes thinner, and when a ball is compressed it becomes fatter: this is what most materials do. However, an auxetic material, in contrast to a rubber band, becomes fatter when stretched, and thinner when compressed. This property is highly unique even compared to other cell nuclei, but we found one other cell type that manifests this same property in its nucleus. That cell type is the oligodendrocyte progenitor cell (OPC), which is similar to ESCs in that they are a self-renewing stem cell. In development, OPCs give rise to oligodendrocytes (the myelinating cell of the central nervous system) and in the adult is responsible for generating new oligodendrocytes following demyelination (a unique and clinically important neural regenerative process called remyelination). Both of these stem cells are keys to regeneration, and we believe our studies will shed new light on how they work. Auxeticity has two important repercussions for the ESC/OPC nucleus. First, it has implications for structure because auxeticity arises from unique structural characteristics (such as the auxetic honeycomb: see https://www.youtube.com/watch?v=vdkYuLsT7Sc). We will use a combination of biotechnology, biological and physics techniques to understand what nuclear structural properties are responsible for auxeticity; in finding this, we will better understand how nuclear structure changes during differentiation, and how these changes might facilitate differentiation. The second repercussion is that auxeticity yields massive volume fluctuations with mechanical stress. Consider that an auxetic nucleus gets fatter when stretched, and thinner when compressed, and it is clear that, unlike most materials, it changes volume considerably with mechanical stress. This, in turn, will cause a large flux of soluble molecules across the nucleus with mechanical stress. Given that, particularly in tissue, stem cells undergo frequent and significant mechanical stress, we believe this is important for how differentiation is regulated. The reason for this is that there are a number of signaling molecules that are necessary for differentiation that are kept outside the nucleus before ESCs or OPCs differentiate. When the mechanically-stressed nucleus significantly swells (we see volume increases in the nucleus of up to 50% with relatively small forces), that will force some of these molecules into the nucleus where they can find their targets. We propose that in this way, auxeticity causes the nucleus to be like a pump for moving molecules across its membrane. We will use the biotechnology we develop to apply mechanical stress to the cells to observe these volume fluctuations and concurrent movement of molecules across the nuclear membrane. We will also use biological techniques to analyse the targets of these molecules to determine if this auxetic effect is causing functional changes in ESCs/OPCs. The research will impact biotechnology, regenerative medicine and stem cell biology. It will bring to bear new insight into how stem cells work, and how we can investigate them. Using our connections in stem cells, biophysics, and biotechnology, we will widely circulate our results, generating impact in several academic disciplines. Given its high potential for impact and its highly cross-disciplinary nature, the proposed research is highly suited for the portfolio of the BBSRC.

胚胎干细胞（ESC）在多能性状态下自我更新，这意味着它们可以产生所有组织类型;因此，它们在再生医学方面非常有前途。我们最近发现它们有一个非常有趣和令人惊讶的特性。就像ESC开始离开这种多能性状态一样-即当它分化时-它们的细胞核，细胞中容纳所有遗传物质的大型结构，变得“生长”。弹性是指材料在机械应力下的响应的性质。考虑一下，在机械应力下，拉紧的橡皮筋变得更薄，而当球被压缩时，它变得更胖：这是大多数材料所做的。然而，与橡皮筋相反，拉胀材料在拉伸时变得更厚，并且在压缩时变得更薄。即使与其他细胞核相比，这种特性也是非常独特的，但我们发现另一种细胞类型在其细胞核中表现出相同的特性。这种细胞类型是少突胶质细胞祖细胞（OPC），它类似于ESCs，因为它们是一种自我更新的干细胞。在发育过程中，OPC产生少突胶质细胞（中枢神经系统的髓鞘形成细胞），并且在成人中负责在脱髓鞘后产生新的少突胶质细胞（一种独特且临床上重要的神经再生过程，称为髓鞘再生）。这两种干细胞都是再生的关键，我们相信我们的研究将为它们如何工作提供新的线索。对ESC/OPC核心来说，遗传性有两个重要的影响。首先，它对结构有影响，因为拉胀性来自于独特的结构特征（如拉胀蜂窝：见https://www.youtube.com/watch? v=vdkYuLsT7Sc）。我们将使用生物技术，生物学和物理学技术相结合，以了解什么样的核结构特性是负责生长;在找到这一点，我们将更好地了解核结构如何在分化过程中变化，以及这些变化如何可能促进分化。第二个影响是，在机械应力作用下，膨胀性产生了巨大的体积波动。考虑到拉胀核在拉伸时变胖，在压缩时变薄，很明显，与大多数材料不同，它的体积随着机械应力而显著变化。这反过来又会导致大量可溶性分子在机械应力作用下穿过细胞核。鉴于干细胞，特别是在组织中，会经历频繁和显著的机械应力，我们认为这对于如何调节分化很重要。这是因为在ESC或OPCs分化之前，有许多分化所必需的信号分子被保留在细胞核外。当受到机械应力的细胞核显著膨胀时（我们看到细胞核的体积增加了50%，力相对较小），这将迫使其中一些分子进入细胞核，在那里它们可以找到它们的目标。我们提出，在这种方式下，膨胀性导致细胞核就像一个泵，使分子穿过细胞膜。我们将使用我们开发的生物技术对细胞施加机械应力，以观察这些体积波动和分子穿过核膜的同时运动。我们还将使用生物技术来分析这些分子的靶点，以确定这种拉胀效应是否导致ESCs/OPCs的功能变化。这项研究将影响生物技术、再生医学和干细胞生物学。它将为干细胞如何工作以及我们如何研究它们带来新的见解。利用我们在干细胞，生物物理学和生物技术方面的联系，我们将广泛传播我们的成果，在多个学科产生影响。鉴于其影响力和高度跨学科的性质，拟议的研究非常适合BBSRC的投资组合。