细胞核结构与力学生物学
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国家自然科学基金(30770534,30270359)


The Nucleus Structure and Mechanotransduction
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    摘要:

    机体所有的组织都受到由细胞自身和细胞外环境所产生的生物机械力(Biomechanical force)的作用。生物机械力既可诱导细胞增殖,亦可诱导细胞死亡。而生理学水平的生物机械力是器官的结构与功能发育和维持的必要条件之一,提高生物机械力则可导致细胞死亡,引发机体一系列病理学变化。在真核细胞中,细胞核含有染色体组,是转录调节场所。细胞核是最大和最硬的细胞器。细胞核一方面承受通过细胞骨架所传递的来至于细胞外部的生物机械力作用,同时也承受由细胞内部所产生的生物机械力作用。在这里,我们复习了细胞内与细胞外的生物机械力对细胞核形状和结构的影响;以及这些生物机械力诱导的变化如何转变为细胞信号传导和基因转录。复习了细胞核和核结构蛋白的力学研究,诸如,核纤层蛋白(Lamins)。在核纤层蛋白突变或缺失的细胞中,如遗传工程化小鼠,RNA干扰研究,或人类疾病,可以观察到这些细胞核的形状、结构和刚度(硬度)发生了令人惊异的变化。我们也着重讨论了在整个发育、生理和病理变化过程中,细胞核形状变化和细胞功能改变之间的联系。这些研究均提示,在细胞对生物机械力刺激的反应中,细胞核自身具有重要的作用。在生物体生长发育的很多重要的进程中,如发育,分化,成熟和衰老,细胞核的形状和结构组成均会发生变化。在这些进程中,细胞通过改变细胞核内基因表达,实现对生物机械力的应答反应。然而,细胞核自身如何感知力学信号并对其发生应答反应,仍不清楚。除了外部生物机械力的作用,细胞核内染色质结构的后天性修饰也会改变核的物理性质。在这里,我们回顾了当前关于细胞核结构与细胞核力学生物学的相关文献以及它们的研究现状。但要更深入地了解核结构和核材料性质与细胞核力学生物学间的关系,了解生物机械力与基因组相互作用的直接机制,细胞核的形状如何与力传导相关,则需要进一步系统地深入地研究。

    Abstract:

    All tissues in the body are subjected to biomechanical force originating either from tension, created by cells themselves, or from the environment. Biomechanical force not only can induce cell proliferation, but also induce cell death. While biomechanical force at physiological levels is essential to develop and maintain organic structure and function, elevated mechanical stress may result in cell death leading to pathological conditions. In eukaryotic cells, the nucleus contains the genome and is the site of transcriptional regulation. The nucleus is the largest and stiffest organelle and is exposed to mechanical forces transmitted through the cytoskeleton from outside the cell and from force generation within the cell. Here, we discuss the effect of intra- and extracellular forces on nuclear shape and structure and how these force-induced changes could be implicated in nuclear mechanotransduction, ie, force-induced changes in cell signaling and gene transcription. We review mechanical studies of the nucleus and nuclear structural proteins, such as lamins. Dramatic changes in nuclear shape, organization, and stiffness are seen in cells where lamin proteins are mutated or absent, as in genetically engineered mice, RNA interference studies, or human disease.. We also highlight studies that link changes in nuclear shape with cell function during developmental, physiological, and pathological modifications. Together, these studies suggest that the nucleus itself may play an important role in the response of the cell to force. Therefore, mechanical stimuli must be sensed by cells and transmitted through intracellular signal transduction pathways to the nucleus. Changes in the shape and structural organization of the cell nucleus occur during many fundamental processes including development, differentiation , mature and aging. In many of these processes, the cell responds to biomechanical force by altering gene expression within the nucleus. However, how the nucleus itself senses and responds to such mechanical cues is not well understood. In addition to these external forces, epigenetic modifications of chromatin structure inside the nucleus could also alter its physical properties. Here we review our current literatures in related to the structure and mechanobiology of cellular nucleus. To achieve a better understanding the relationship between the mechanobiology of cell nucleus and the nuclear material properties, we need to do more research ranging from molecule to tissue.

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李良,陈槐卿.细胞核结构与力学生物学[J].医用生物力学,2009,24(1):1-5

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